阿托伐他汀联合辅酶Q10抑制心室重构的作用机制
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摘要
心室重构是心力衰竭(heart failure,HF)发展的基础，而非梗死区心肌重构在心衰的发展中占有重要地位。HF后的能量代谢障碍可能是心室扩大和功能异常的主要原因，进而导致心室重构，心肌能量代谢障碍与心室重构形成恶性循环，促进心衰的发生发展。因此，调节心脏的能量代谢有可能成为治疗心衰的一种新方法。线粒体是能量产生和储存的主要场所，线粒体功能障碍是HF心肌代谢紊乱的核心。因此，研究衰竭心肌线粒体改变对揭示HF能量代谢及心室重构的机制具有重要意义。解耦联蛋白(uncoupling proteins,UCPs)位于线粒体内膜上，是参与能量代谢的重要转运蛋白，其中UCP2主要在心肌中表达，参与能量代谢、凋亡、活性氧的生成等过程，并与动脉粥样硬化、缺血/再灌注损伤、肥胖及2型糖尿病等有着密切的关系。目前对心肌生理状态下UCP2的研究较多，但心力衰竭时非梗死区心室重构与UCP2的表达变化之间的关系如何，目前还未见报道。辅酶Q10是生物体内广泛存在的脂溶性醌类化合物，作为心肌线粒体内膜的一种递氢体，参于电子传递过程，是细胞呼吸和代谢的激活剂。已有研究表明，充血性心力衰竭病人心肌内源性辅酶Q10含量低于正常水平，并通过对心肌活检表明，心衰程度越严重的患者，其心肌辅酶Q10含量越低，外源性补充辅酶Q10后能够明显改善心功能。阿托伐他汀是一种3-羟基3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂，通过抑制HMG-CoA还原酶活性使胆固醇的合成减少，主要作用部位在肝脏。该药物还能通过增加肝细胞表面低密度脂蛋白（LDL）受体数目而增加LDL的摄取和分解代谢，主要用来降低冠状动脉粥样硬化性心脏病人的血脂水平，但他汀类非降脂作用越来越引起人们的重视。众多的临床研究及动物实验表明他汀类及辅酶Q10在治疗心血管疾病中的重要地位，尤其在心力衰竭方面的有益作用日益受到密切关注。但他汀类联合应用辅酶Q10在心梗后心衰模型中能否够通过干预能量代谢及相关基因UCP2的表达，进而影响非梗死区心肌重塑，目前尚不清楚。因此，本实验首先通过体内实验观察联合应用阿托伐他汀及辅酶Q10对心梗后心衰大鼠心肌能量代谢及其相关基因UCP2表达的影响，进一步探究其对非梗死区心肌重构的影响机制。其次，通过体外实验研究联合应用阿托伐他汀及辅酶Q10对Ang II诱导的心肌细胞及心肌成纤维细胞能量代谢相关基因UCP2表达及心肌胶原分泌的影响，从整体、细胞和分子水平探讨联合应用阿托伐他汀及辅酶Q10干预心梗后心衰能量代谢及心室重构的机制，为心衰发病机制的研究、治疗及寻找更合理的联合用药方案来改善心衰提供理论依据。
方法：
通过结扎Wistar大鼠左冠状动脉前降支(left anterior descending artery,LAD)6周建立心梗后心衰模型。结扎LAD48h后，大鼠尾静脉取血0.5ml，ELISA法检测cTnT水平，模型组cTnT水平为假手术组上限水平的3倍，为cTnT水平升高有意义，以证明急性心梗模型建立成功。存活的大鼠按体重随机分为假手术组、模型组、阿托伐他汀组及阿托伐他汀-辅酶Q10组，共4组，每组6只。后两组按分组要求连续灌胃给药5w后检测以下指标：应用HE染色、Masson染色及进一步电镜检测，观察各组大鼠左室非梗死区心肌形态学的变化；血流动力学检测LVSP、LVEDP和±dp/dtmax等变化情况；全心肥厚指数及左心肥厚指数测定；ELISA方法测血浆中BNP水平，血清Ang II及左室非梗死区心肌组织ATP含量，血清琥珀酸脱氢酶(succinodehydrogenase,SDH)及细胞色素C氧化酶(cytochrome coxidase,CcO)活性；化学比色法测定血清MDA、乳酸及游离脂肪酸含量，血清SOD、非梗死区心肌组织钠钾ATP酶、钙镁ATP酶活性；应用RT-PCR法检测左室非梗死区心肌组织胶原蛋白I(col-I)、胶原蛋白IIII (col-III)及UCP2mRNA表达水平，以及测定col-I/col-III比值。免疫组化法检测左室非梗死区心肌组织胶原蛋白I(col-I)、胶原蛋白IIII (col-III)及UCP2蛋白表达；Western bloting进一步检测左室非梗死区心肌组织UCP2蛋白表达。
体外培养出生24小时内Wistar乳鼠的心肌细胞，以Ang II诱导心肌细胞肥大，并分别给予外源性阿托伐他汀及阿托伐他汀-辅酶Q10干预，检测以下指标：心肌细胞的表面积；心肌细胞的总蛋白质含量；Western bloting检测心肌细胞UCP2蛋白表达。此外，体外培养出生24小时内Wistar乳鼠的心肌成纤维细胞，以Ang II诱导心肌成纤维细胞增殖，并分别给予外源性阿托伐他汀及阿托伐他汀-辅酶Q10干预，检测以下指标：心肌成纤维细胞增殖数量；培养液上清羟脯氨酸含量测定；Western bloting检测心肌成纤维细胞col-I及col-III蛋白表达。
结果：
1、动物实验研究结果表明，与假手术组比较，模型组大鼠心脏体积明显增大，已不能维持正常几何形状，心室腔明显扩大，偶有室壁瘤形成；心肌细胞排列紊乱，心肌间质大量纤维组织增生。同时血流动力学明显改变，LVEDP增高，LVSP和±dp/dt max明显降低。与模型对照组比较，阿托伐他汀组心脏基本能维持正常几何形状，心室腔扩张程度减轻；心肌细胞排列较整齐，心肌间质纤维增生程度减弱。
2、阿托伐他汀能够降低LVEDP，增高LVSP和±dp/dtmax，改善血流动力学状态。
3、与模型组相比，阿托伐他汀组能够降低心肌肥厚指数，减轻左室非梗死区心肌组织病理学改变及线粒体超微结构损伤，
4、降低与心室重构相关的介质血浆BNP和血清AngII水平，有效减少血清MDA、乳酸及游离脂肪酸堆积，提高SDH、CcO、SOD、钠钾ATP酶、钙镁ATP酶活性及左室非梗死区心肌组织ATP含量，下调左室非梗死区心肌组织col-I、col-III及UCP2mRNA及蛋白表达水平。
以上结果阿托伐他汀-辅酶Q10组与阿托伐他汀组之间相比，有效果更佳的趋势。
5、体外实验表明，与肥大细胞模型组相比，阿托伐他汀组及阿托伐他汀-辅酶Q10组能够减少肥大的心肌细胞表面积、降低其总蛋白质含量及抑制肥大的心肌细胞UCP2蛋白表达；与增殖模型组相比，阿托伐他汀组及阿托伐他汀-辅酶Q10组能够抑制心肌成纤维细胞增殖，降低培养液上清羟脯氨酸含量及抑制增殖的心肌成纤维细胞col-I及col-III蛋白表达，减少胶原沉积。而且，阿托伐他汀-辅酶Q10组与阿托伐他汀组之间相比，有作用效果更佳的趋势。
结论：
1、心梗后心衰时存在氧化应激损伤并参与心室重构，阿托伐他汀能够降低MDA、乳酸及游离脂肪酸含量、提高SOD活性，具有抗氧化作用。
2、心梗后心衰时存在能量代谢障碍，阿托伐他汀可以提高SDH、CcO、Na~+-K~+ATP酶、Ca~(2+)-Mg~(2+)ATP酶活性，升高非梗死区心肌局部组织ATP含量。
3、阿托伐他汀干预能量代谢抑制心室重构的机制与调节UCP2蛋白表达有关。高表达的UCP2可能是导致心梗后心肌纤维化并诱发心衰的重要因素。
4、以上结果在联合辅酶Q10组有效果更好的趋势，提示辅酶Q10对阿托伐他汀干预心衰心肌能量代谢有正面的影响。具体机制有待进一步探讨。
It is known that ventricular remodeling is the pathological basis of heart failuredevelopment,and the non-infarced area of left ventricular remodeling plays animportant role in the pathogenic process of heart failure. After heart failure,energymetabolization obstacle may be ventricular enlargement and cardiac anomalies of themain reasons,which lead to myocardial remodeling,and then have a vicious circle ofmyocardial energy metabolism disorder and myocardial remodeling,which promotethe occurrence and development of heart failure. Therefore,regulating the cardiacenergy metabolism may become a new method in treatment of heartfailure.Mitochondria are the main organelles of energy generation and storage,mitochondria dysfunction is the core of myocardial metabolic disorders after heartfailure.Therefore,study of myocardial mitochondrial changes to reveal heart failureenergy metabolism and ventricular remodeling mechanisms has an importantsignificance.Uncoupling protein2(UCP2) is a transport protein and expression inmyocardium that is located in the mitochondrial inner membrane,involved in energymetabolism, apoptosis, the production of reactive oxygen species, furthermore,atherosclerosis, ischemia/reperfusion injury, obesity and type2diabetes.Currently,the studies of the UCP2expression in myocardium under physiological conditionmore,but the changes of UCP2expressions in non-infarced area after heart failure andthe relationship between the changes of UCP2expression in heart failure and innon-infarced area ventricular remodeling, at present have not beenreported.Coenzyme Q10is a fatsoluble organic quinones compound widely existing inthe living body, which is cellular respiration and metabolic activator as a hydrogencarrier for participating in the electron transfer process. Studies have shown thatmyocardial endogenous coenzyme Q10content in patients with congestive heartfailure is lower than the normal level, and through to the myocardial biopsy isindicated that the level of coenzyme Q10was positively correlated to the the degreeof heart failure patients,and exogenous coenzyme Q10also could significantlyimprove cardiac function. Atorvastatin is a hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor(statins)，widely used in coronary atherosclerosisheart disease to reduce blood lipids by inhibiting HMG-CoA reductase, which is thebiosynthesis of cholesterol in the liver,and increasing the number of low densitylipoprotein (LDL) receptor on liver cell surface,furthermore, increasing LDL uptakeand catabolism.But, more and more people concerned about the problems which arethe nonlipid effections of statins.An increasing number of clinical studies and animalexperiments show that statins and coenzyme Q10play an important role in thetreatment of cardiovascular diseases,which are the beneficial effects, especially inheart failure arouses more attentions. However it is unclear that statins combinedcoenzyme Q10effects on the non-infarced area of left ventricular remodeling byintervening energy metabolism and the expression changes of UCP2gene in heartfailure after acute myocardial infarction.Therefore, fistly, we explored the effects ofatorvastatin combined coenzyme Q10on energy metabolism and its related geneexpression changes of UCP2, and further probed into the non-infarced area of leftventricular remodeling in heart failure after acute myocardial infarction inrats.Secondly, we observed the effects of atorvastatin combined coenzyme Q10onAngII induced myocardial cells and cardiac fibroblasts energy metabolism relatedgene UCP2expression and myocardial remodeling in vitro. Our research observed theeffects and mechanisms of atorvastatin combined coenzyme Q10on energymetabolism and ventricular remodeling from whole and molecular level to cellular toprovide a theoretical basis in heart failure mechanisms,pathogenesis,treatment andfind more reasonable combination schemes to improves heart function.The mainresearch contents are as follows:
Methods:
Heart failure in female Wistar rat models were created by ligating left arterydescending(LAD) last6weeks. All the rats were drawed blood from the tail vein0.5ml after the surgery by ligating left artery descending in48hours,the levels ofcTnT were measured by ELISA to prove to build a successful animal model of acutemyocardial infarction,and it is significant that the Level cTnT of model group was3times for cTnT elevated levels of meaning.Survival of rats were randomly dividedinto sham operation group, model group, atorvastatin group and atorvastatin-coenzyme Q10group,6rats in each group.Continuous intragastric administration ofdrug over5weeks,we observed the changes of the non-infarced area of left ventricular on morphology of rat myocardium by using HE staining, Masson stainingand further electron microscopic detection; we also measured the changes ofhaemodynamics, such as left ventricular end-diastolic pressure (LVEDP),leftventricular systolic pressure(LVSP),+dp/dtmaxand-dp/dtmaxof left ventricularpressure;the whole heart hypertrophy index and left ventricular hypertrophy indexwere determined; in addition,the levels of BNP in plasma,the levels of Ang II inserum,the content of ATP in the non-infarced area of left ventricular,the activities ofsuccinodehydrogenase and cytochrome coxidase were quantified with ELISA;thecontents of MDA, lactate and free fatty acid,the activities of SOD,Na+-K+ATPase,Ca+-Mg+ATPase with chemical colorimetry were obtained.The expressions ofcol-I,col-III and UCP2mRNA was detected by RT-PCR in the non-infarced area ofleft ventricular,and the results of col-I/col-III were calculated.We also assayed theprotein expressions of col-I, col-III and UCP2by using immunohistochemical method,Furthermore, the protein expressions of UCP2in the non-infarced area of leftventricular by western bloting.
Cardiomyocyte from neonatal rat were cultured in vitro,and researched theinhibition effects of atorvastatin and atorvastatin combined with coenzyme Q10oncardiomyocyte hypertrophy induced by angiotensin II.After24h,we examined themyocytes’ surface area,the content of total protein in Cardiomyocyte,furthermore, theprotein expressions of UCP2by western bloting assay. In addition, cardiac fibroblastsfrom neonatal rat were cultured in vitro,and researched the inhibition effects ofatorvastatin and atorvastatin combined with coenzyme Q10on on cardiac fibroblastsproliferation induced by angiotensin II.After24h, we analysed the quantities ofcardiac fibroblasts proliferation, the contents of hydroxyproline in the culturesupernatant,and the protein expressions of col-I and col-III by western bloting.
Results:
1、We succeeded in making heart failure rat models after myocardial infarction byligating LAD,compared with the sham operation group, cardiac enlargement, has notbeen able to maintain the normal geometry, ventricular chamber enlargement,occasionally left ventricular aneurysm in operation groups,and myocardial cellsarranged in disorder, myocardial interstitial fibrous tissue proliferation. Furthermore,hemodynamic changes,such asLVEDP were increased,LVSP and±dp/dtmax reduced.compared with the operation group.Atorvastatin group heart could basically maintain the normal shape, and reduced the degree of ventricular dilation; myocardial cellswere arranged in order, the degree of interstitial fibrosis decreased myocardial.
2、Atorvastatin could decrease LVEDP, increase LVSP and±dp\/dtmax, improved thehemodynamic status.
3、Compared with the operation group, atorvastatin could reduce the myocardialhypertrophy index, left ventricular non injury and mitochondrial ultrastructurepathological myocardial in Left ventricular non-infarcted zone.
4、Furthermore, atorvastatin reduced the associated with ventricular remodeling inmedium of plasma BNP,serum AngII levels, serum MDA, lactate and free fatty acidaccumulation. In serum,elevated the levels of SDH,CcO,SOD,,Na＋-K＋ATPase,Ca2+-Mg2+ATPase, and the content of ATP in the non-infarced area of leftventricular were increased. moreover,down-regulated the express of proteins andmRNA of UCP2, col-I、col-III in Left ventricular non-infarcted zone.
The above results between atorvastatin statins-coenzyme Q10group andatorvastatin group compared with better effect trend.5、In vitro, Compared with the hypertrophy model group,atorvastatin and atorvastatincombined with coenzyme Q10could deflate myocytes’ surface area,and then,coulddecrease the content of total protein,down-regulated the expreess of proteins ofUCP2by AngII induced.In addition, Compared with the cardiac fibroblastsproliferation group,there were obviously inhibition effects on cardiac fibroblastsproliferation,collagen secretion,and the protein expressions of col-I,col-III. Moreover,effects of atorvastatin-coenzyme Q10group were better than atorvastatin.
Conclusions：
1、Heart failure after myocardial infarction are involved in oxidative stress injury andventricular remodeling, atorvastatin can decrease MDA, lactate and free fatty acidcontent, improve the activity of SOD, anti-oxidation.
2、there is energy metabolism disorder of heart failure after myocardial infarction,atorvastatin can improve SDH, CcO, Na+-K+ATP enzyme and Ca2+-Mg2+ATPenzyme activity, and increased the content of ATP in local tissue non-infarctedmyocardium significantly.
3、Atorvastatin energy metabolism inhibition mechanism of ventricular remodelingand regulation of UCP2protein expression. The high expression of UCP2may be an important factor in myocardial fibrosis and heart failure after myocardial infarction.
4、The above results has better effect in combined with coenzyme Q10group trend,suggesting coenzyme Q10have positive effect of heart failure myocardial energymetabolism of atorvastatin. The specific mechanism need further study.
方法：
通过结扎Wistar大鼠左冠状动脉前降支(left anterior descending artery,LAD)6周建立心梗后心衰模型。结扎LAD48h后，大鼠尾静脉取血0.5ml，ELISA法检测cTnT水平，模型组cTnT水平为假手术组上限水平的3倍，为cTnT水平升高有意义，以证明急性心梗模型建立成功。存活的大鼠按体重随机分为假手术组、模型组、阿托伐他汀组及阿托伐他汀-辅酶Q10组，共4组，每组6只。后两组按分组要求连续灌胃给药5w后检测以下指标：应用HE染色、Masson染色及进一步电镜检测，观察各组大鼠左室非梗死区心肌形态学的变化；血流动力学检测LVSP、LVEDP和±dp/dtmax等变化情况；全心肥厚指数及左心肥厚指数测定；ELISA方法测血浆中BNP水平，血清Ang II及左室非梗死区心肌组织ATP含量，血清琥珀酸脱氢酶(succinodehydrogenase,SDH)及细胞色素C氧化酶(cytochrome coxidase,CcO)活性；化学比色法测定血清MDA、乳酸及游离脂肪酸含量，血清SOD、非梗死区心肌组织钠钾ATP酶、钙镁ATP酶活性；应用RT-PCR法检测左室非梗死区心肌组织胶原蛋白I(col-I)、胶原蛋白IIII (col-III)及UCP2mRNA表达水平，以及测定col-I/col-III比值。免疫组化法检测左室非梗死区心肌组织胶原蛋白I(col-I)、胶原蛋白IIII (col-III)及UCP2蛋白表达；Western bloting进一步检测左室非梗死区心肌组织UCP2蛋白表达。
体外培养出生24小时内Wistar乳鼠的心肌细胞，以Ang II诱导心肌细胞肥大，并分别给予外源性阿托伐他汀及阿托伐他汀-辅酶Q10干预，检测以下指标：心肌细胞的表面积；心肌细胞的总蛋白质含量；Western bloting检测心肌细胞UCP2蛋白表达。此外，体外培养出生24小时内Wistar乳鼠的心肌成纤维细胞，以Ang II诱导心肌成纤维细胞增殖，并分别给予外源性阿托伐他汀及阿托伐他汀-辅酶Q10干预，检测以下指标：心肌成纤维细胞增殖数量；培养液上清羟脯氨酸含量测定；Western bloting检测心肌成纤维细胞col-I及col-III蛋白表达。
结果：
1、动物实验研究结果表明，与假手术组比较，模型组大鼠心脏体积明显增大，已不能维持正常几何形状，心室腔明显扩大，偶有室壁瘤形成；心肌细胞排列紊乱，心肌间质大量纤维组织增生。同时血流动力学明显改变，LVEDP增高，LVSP和±dp/dt max明显降低。与模型对照组比较，阿托伐他汀组心脏基本能维持正常几何形状，心室腔扩张程度减轻；心肌细胞排列较整齐，心肌间质纤维增生程度减弱。
2、阿托伐他汀能够降低LVEDP，增高LVSP和±dp/dtmax，改善血流动力学状态。
3、与模型组相比，阿托伐他汀组能够降低心肌肥厚指数，减轻左室非梗死区心肌组织病理学改变及线粒体超微结构损伤，
4、降低与心室重构相关的介质血浆BNP和血清AngII水平，有效减少血清MDA、乳酸及游离脂肪酸堆积，提高SDH、CcO、SOD、钠钾ATP酶、钙镁ATP酶活性及左室非梗死区心肌组织ATP含量，下调左室非梗死区心肌组织col-I、col-III及UCP2mRNA及蛋白表达水平。
以上结果阿托伐他汀-辅酶Q10组与阿托伐他汀组之间相比，有效果更佳的趋势。
5、体外实验表明，与肥大细胞模型组相比，阿托伐他汀组及阿托伐他汀-辅酶Q10组能够减少肥大的心肌细胞表面积、降低其总蛋白质含量及抑制肥大的心肌细胞UCP2蛋白表达；与增殖模型组相比，阿托伐他汀组及阿托伐他汀-辅酶Q10组能够抑制心肌成纤维细胞增殖，降低培养液上清羟脯氨酸含量及抑制增殖的心肌成纤维细胞col-I及col-III蛋白表达，减少胶原沉积。而且，阿托伐他汀-辅酶Q10组与阿托伐他汀组之间相比，有作用效果更佳的趋势。
结论：
1、心梗后心衰时存在氧化应激损伤并参与心室重构，阿托伐他汀能够降低MDA、乳酸及游离脂肪酸含量、提高SOD活性，具有抗氧化作用。
2、心梗后心衰时存在能量代谢障碍，阿托伐他汀可以提高SDH、CcO、Na~+-K~+ATP酶、Ca~(2+)-Mg~(2+)ATP酶活性，升高非梗死区心肌局部组织ATP含量。
3、阿托伐他汀干预能量代谢抑制心室重构的机制与调节UCP2蛋白表达有关。高表达的UCP2可能是导致心梗后心肌纤维化并诱发心衰的重要因素。
4、以上结果在联合辅酶Q10组有效果更好的趋势，提示辅酶Q10对阿托伐他汀干预心衰心肌能量代谢有正面的影响。具体机制有待进一步探讨。
It is known that ventricular remodeling is the pathological basis of heart failuredevelopment,and the non-infarced area of left ventricular remodeling plays animportant role in the pathogenic process of heart failure. After heart failure,energymetabolization obstacle may be ventricular enlargement and cardiac anomalies of themain reasons,which lead to myocardial remodeling,and then have a vicious circle ofmyocardial energy metabolism disorder and myocardial remodeling,which promotethe occurrence and development of heart failure. Therefore,regulating the cardiacenergy metabolism may become a new method in treatment of heartfailure.Mitochondria are the main organelles of energy generation and storage,mitochondria dysfunction is the core of myocardial metabolic disorders after heartfailure.Therefore,study of myocardial mitochondrial changes to reveal heart failureenergy metabolism and ventricular remodeling mechanisms has an importantsignificance.Uncoupling protein2(UCP2) is a transport protein and expression inmyocardium that is located in the mitochondrial inner membrane,involved in energymetabolism, apoptosis, the production of reactive oxygen species, furthermore,atherosclerosis, ischemia/reperfusion injury, obesity and type2diabetes.Currently,the studies of the UCP2expression in myocardium under physiological conditionmore,but the changes of UCP2expressions in non-infarced area after heart failure andthe relationship between the changes of UCP2expression in heart failure and innon-infarced area ventricular remodeling, at present have not beenreported.Coenzyme Q10is a fatsoluble organic quinones compound widely existing inthe living body, which is cellular respiration and metabolic activator as a hydrogencarrier for participating in the electron transfer process. Studies have shown thatmyocardial endogenous coenzyme Q10content in patients with congestive heartfailure is lower than the normal level, and through to the myocardial biopsy isindicated that the level of coenzyme Q10was positively correlated to the the degreeof heart failure patients,and exogenous coenzyme Q10also could significantlyimprove cardiac function. Atorvastatin is a hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor(statins)，widely used in coronary atherosclerosisheart disease to reduce blood lipids by inhibiting HMG-CoA reductase, which is thebiosynthesis of cholesterol in the liver,and increasing the number of low densitylipoprotein (LDL) receptor on liver cell surface,furthermore, increasing LDL uptakeand catabolism.But, more and more people concerned about the problems which arethe nonlipid effections of statins.An increasing number of clinical studies and animalexperiments show that statins and coenzyme Q10play an important role in thetreatment of cardiovascular diseases,which are the beneficial effects, especially inheart failure arouses more attentions. However it is unclear that statins combinedcoenzyme Q10effects on the non-infarced area of left ventricular remodeling byintervening energy metabolism and the expression changes of UCP2gene in heartfailure after acute myocardial infarction.Therefore, fistly, we explored the effects ofatorvastatin combined coenzyme Q10on energy metabolism and its related geneexpression changes of UCP2, and further probed into the non-infarced area of leftventricular remodeling in heart failure after acute myocardial infarction inrats.Secondly, we observed the effects of atorvastatin combined coenzyme Q10onAngII induced myocardial cells and cardiac fibroblasts energy metabolism relatedgene UCP2expression and myocardial remodeling in vitro. Our research observed theeffects and mechanisms of atorvastatin combined coenzyme Q10on energymetabolism and ventricular remodeling from whole and molecular level to cellular toprovide a theoretical basis in heart failure mechanisms,pathogenesis,treatment andfind more reasonable combination schemes to improves heart function.The mainresearch contents are as follows:
Methods:
Heart failure in female Wistar rat models were created by ligating left arterydescending(LAD) last6weeks. All the rats were drawed blood from the tail vein0.5ml after the surgery by ligating left artery descending in48hours,the levels ofcTnT were measured by ELISA to prove to build a successful animal model of acutemyocardial infarction,and it is significant that the Level cTnT of model group was3times for cTnT elevated levels of meaning.Survival of rats were randomly dividedinto sham operation group, model group, atorvastatin group and atorvastatin-coenzyme Q10group,6rats in each group.Continuous intragastric administration ofdrug over5weeks,we observed the changes of the non-infarced area of left ventricular on morphology of rat myocardium by using HE staining, Masson stainingand further electron microscopic detection; we also measured the changes ofhaemodynamics, such as left ventricular end-diastolic pressure (LVEDP),leftventricular systolic pressure(LVSP),+dp/dtmaxand-dp/dtmaxof left ventricularpressure;the whole heart hypertrophy index and left ventricular hypertrophy indexwere determined; in addition,the levels of BNP in plasma,the levels of Ang II inserum,the content of ATP in the non-infarced area of left ventricular,the activities ofsuccinodehydrogenase and cytochrome coxidase were quantified with ELISA;thecontents of MDA, lactate and free fatty acid,the activities of SOD,Na+-K+ATPase,Ca+-Mg+ATPase with chemical colorimetry were obtained.The expressions ofcol-I,col-III and UCP2mRNA was detected by RT-PCR in the non-infarced area ofleft ventricular,and the results of col-I/col-III were calculated.We also assayed theprotein expressions of col-I, col-III and UCP2by using immunohistochemical method,Furthermore, the protein expressions of UCP2in the non-infarced area of leftventricular by western bloting.
Cardiomyocyte from neonatal rat were cultured in vitro,and researched theinhibition effects of atorvastatin and atorvastatin combined with coenzyme Q10oncardiomyocyte hypertrophy induced by angiotensin II.After24h,we examined themyocytes’ surface area,the content of total protein in Cardiomyocyte,furthermore, theprotein expressions of UCP2by western bloting assay. In addition, cardiac fibroblastsfrom neonatal rat were cultured in vitro,and researched the inhibition effects ofatorvastatin and atorvastatin combined with coenzyme Q10on on cardiac fibroblastsproliferation induced by angiotensin II.After24h, we analysed the quantities ofcardiac fibroblasts proliferation, the contents of hydroxyproline in the culturesupernatant,and the protein expressions of col-I and col-III by western bloting.
Results:
1、We succeeded in making heart failure rat models after myocardial infarction byligating LAD,compared with the sham operation group, cardiac enlargement, has notbeen able to maintain the normal geometry, ventricular chamber enlargement,occasionally left ventricular aneurysm in operation groups,and myocardial cellsarranged in disorder, myocardial interstitial fibrous tissue proliferation. Furthermore,hemodynamic changes,such asLVEDP were increased,LVSP and±dp/dtmax reduced.compared with the operation group.Atorvastatin group heart could basically maintain the normal shape, and reduced the degree of ventricular dilation; myocardial cellswere arranged in order, the degree of interstitial fibrosis decreased myocardial.
2、Atorvastatin could decrease LVEDP, increase LVSP and±dp\/dtmax, improved thehemodynamic status.
3、Compared with the operation group, atorvastatin could reduce the myocardialhypertrophy index, left ventricular non injury and mitochondrial ultrastructurepathological myocardial in Left ventricular non-infarcted zone.
4、Furthermore, atorvastatin reduced the associated with ventricular remodeling inmedium of plasma BNP,serum AngII levels, serum MDA, lactate and free fatty acidaccumulation. In serum,elevated the levels of SDH,CcO,SOD,,Na＋-K＋ATPase,Ca2+-Mg2+ATPase, and the content of ATP in the non-infarced area of leftventricular were increased. moreover,down-regulated the express of proteins andmRNA of UCP2, col-I、col-III in Left ventricular non-infarcted zone.
The above results between atorvastatin statins-coenzyme Q10group andatorvastatin group compared with better effect trend.5、In vitro, Compared with the hypertrophy model group,atorvastatin and atorvastatincombined with coenzyme Q10could deflate myocytes’ surface area,and then,coulddecrease the content of total protein,down-regulated the expreess of proteins ofUCP2by AngII induced.In addition, Compared with the cardiac fibroblastsproliferation group,there were obviously inhibition effects on cardiac fibroblastsproliferation,collagen secretion,and the protein expressions of col-I,col-III. Moreover,effects of atorvastatin-coenzyme Q10group were better than atorvastatin.
Conclusions：
1、Heart failure after myocardial infarction are involved in oxidative stress injury andventricular remodeling, atorvastatin can decrease MDA, lactate and free fatty acidcontent, improve the activity of SOD, anti-oxidation.
2、there is energy metabolism disorder of heart failure after myocardial infarction,atorvastatin can improve SDH, CcO, Na+-K+ATP enzyme and Ca2+-Mg2+ATPenzyme activity, and increased the content of ATP in local tissue non-infarctedmyocardium significantly.
3、Atorvastatin energy metabolism inhibition mechanism of ventricular remodelingand regulation of UCP2protein expression. The high expression of UCP2may be an important factor in myocardial fibrosis and heart failure after myocardial infarction.
4、The above results has better effect in combined with coenzyme Q10group trend,suggesting coenzyme Q10have positive effect of heart failure myocardial energymetabolism of atorvastatin. The specific mechanism need further study.
引文
[1] Demers C,McMurray JJ.Swedberg K, et a1.Impact of candesartan on nonfatalmyocardial infarction and cardiovascular death in patients with heart failure[J].JAMA,2005,294(14):1794-8.
[2] McMurray JJ,Pfeffer MA.Heart failure[J].Lancet,2005,365(9474):1877-1889.
[3]戴闺柱.2005年美国慢性收缩性心力衰竭治疗指南浅析[J].中华心血管病志,2005,3(12):1065-1066.
[4]张义红.神经内分泌激活与心肌细胞凋亡在心力衰蝎发生发展中的作用及机制[J].心血管病学进展,2001,22:50-53.
[5]史亚非.充血性心力衰竭肾上腺素途径的变化及其临床意义[J].国外医学―心血管分册,1995,326-330.
[6] Antos CL, Frey N, Marx SO, et a1. Dilated cardiomyopathy and sudden deathresulting from constitutive activation of protein kinase A[J]. Circ Res,2001,89(11):997-1004.
[7]崔希忠.交感神经神经系统兴奋在充血性心力衰竭中的临床意义[J].国外医学―心血管分册,1996,23:314-316.
[8] Serneri GG,Boddi M,Cecioni I,et al.Cardiac angiotensin II formation in theclinical course of heart failure and its relationship with left ventricularfunction[J].Circ Res,2001,88(9):961-968.
[9] Miserey S,Clauser E.Angiotensin II receptor:classification,structure and signaltransduction [J].Therapie,1998,53(3):205-11.
[10]Schultz JE,Witt SA,Glascock BJ,et al.TGF-β1mediates the hypertrophiccardiomyocyte growth induced by angiotensin II[J].J Clin Invest,2002,109(6):787-96.
[11]Lijnen P,Petrov V.Renin-angiotensin system,hypertrophy and gene exoression incardiac myocytes[J].J Mol Cell Cardiol,1999,31(5):949-70.
[12]Kawano H, Do YS, Kawano Y, et al.Angiotensin II has multiple prebrothiceffects in human cardiac fibroblasts [J].Circulation,2000,1(10):1130-1137.
[13]ZhangD,GaussinV,SchneiderM D,et al.TAK1is activated in the myocardiumafter pressure overload and is sufficient to provoke heart failure in transgenicmice[J].Nat Med,2000,6(5):556-563.
[14]Mondry A,Swynghedauw B.Bioligical adaption of the myocardium to chronicmechanical overload: Molecular determinant of the autonomic nervous system [J].Eur Heart J,1995,16:64-73.
[15]Starksen NF,Simpson PC,Bishopric N, et al. Cardiac myocyte hypertrophy isassociated with c-myc protooncogene expression [J]. Proc Nati Acad SciUSA,1986,83(21):8348-8350.
[16]Zannad F.Aldostorone and heart failure[J]. Eur heart J,1995,16(suppl N):98-102.
[17]Mc Mahon EG.Recent studies with eplerenone, a novel selective aldosteronereceptor antagonist[J]. Curr Opin Pharmacol,2001,1(2):190-196.
[18]Weber KT,Brilla CG.Pathological hypertrophy and cardiac interstitium: fibrosisand renin-angiotensin-aldosterone system[J].Circulation,1991,83(6):1849-1865.
[19]Nishimura H. Comparative endocrinology of renin and angiotensin[J].Adv ExpMed Biol,1980,130,29-77.
[20]Schohn DC,Jahn HA, Pelletier BC. Dose-related cardiovascular effects ofspironolactone[J]. Am J cardiol,1993,719(3):40A-45A.
[21]Sies H, Brigelius R, Wefers H, et al.Cellular redox changes and response todrugs and toxic agents[J]. Fundam Appl Toxicol,1983,3(4):200-208.
[22]Dominik N Muller,Ralf Dechend,Eero M.A. Mervaala, et al. NF-κB Inhibitionameliorates angiotensin II-induced inflammatory damage in rats[J]. Hypertension,2000,35(1Pt2):193-201.
[23]Poderoso JJ, Carreras MC,Lisdero C, et al. Nitric oxide inhibits electron transferand increases superoxide radical production in rat heart mitochondria andsubmitochondrial particles[J].Arch Biochem Biophys,1996,328(1):85-92.
[24]Han YJ, Kwon YG, ChunghHT, et al. Antioxidant enzymes suppress nitric oxideproduction through the inhibition of NF-κB activation: role of H2O2and nitricoxide in inducible nitric oxide synthase expression in macrophages[J]. NitricOxide,2001,59(5):504-513.
[25]Forman HJ, Torres M, Fukuto J. Redox signaling[J]. Mol Cell Biochem,2002,234-235(1-2):49-62.
[26]Ungvari Z, Orosz Z, Labinskyy N, et al. Increased mitochondrial H2O2production promotes endothelial NF-κB activation in aged rat arteries[J]. Am JPhysiol Heart Circ Physiol,2007,293(4): H37-47.
[27]Li JM, Gall NP, Grieve DJ, et al. Activation of NADPH oxidase duringprogression of cardiac hypertrophy to failure[J]. Hypertension,2002,40(4):477-484.
[28]Higuchi Y, Otsu K, Nishida K, et al. Involvement of reactive oxygen species-mediated NF-κappa B activation in TNF-alpha-induced cardiomyocytehypertrophy[J]. J Mol Cell Cardiol,2002,34(2):233-240.
[29]Xiao L, Pimentel DR, Wang J, et al. Role of reactive oxygen species andNAD(P)H oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiacmyocytes[J]. Am J Physiol Cell Physiol,2002,282(4):926-934.
[30]游琪,蔡久英.氧化应激与心肌损伤的研究进展[J].临床荟萃,2005,20(19):1127-1129.
[31]Pimentel DR,Amin JK,Xiso L, et al.Reactive oxygen species mediateamplitudedependent hypertrophic and apoptotic responses to mechanical stretchin cardiac myocytes[J]. Ciro Res,2001,89(5):453-460.
[32]Li M, Georgakopoulos D, Lu G, et al. p38MAP Kinase mediates inflammatorycytokine induction in cardiomyocytes and extracellular matrix remodeling inheart[J]. Circulation,2005,111(19):2494-2502.
[33]Gill C, Mestril R, Samali A. Losing heart:the role of apoptosis in heartdiseasea-a novel therapeutic target?[J].FASEB J,2002,16(2):135-146.
[34]Ruixinq Y,Dezhai Y,Jiaquan L.Effects of cardiotrophin-1on hemodynamics andcardiomyocyte apoptosis in rats with acute myocardial infarction[J].J MedInvest,2004,51(1-2):29-37.
[35]SperrWR,Bankl HC,Mundiqler G,et al.The human cardiac mast cell:localization,isolation,phenotype,and functional characterization[J]. Blood,1994,84(11):3876-3884.
[36]Hara M,Matsumori A,Ono K,etal.Mast cells cause apoptosis of cardiomyocytesand proliferation of other intramyocardial cells in vitro[J].Circulation,1999,100(13):1443-1449
[37]Thorburn A.Death receptor-induced cell killing[J].Cell Signal,2004,170(6):3118-3124.
[38]Liao X,Wang X,GU Y,et al. Involvement of death receptor signaling inmechanical stretch-induced cardiomyocyte apoptosis[J].Life Sci,2005,77(2):160-
[39]Hartford M,Wiklund O,Mattsson Hulten L, et al.C-reactive protein,interleukin-6,secretory phospholipase A2group II A and intercellular adhesion molecule-1inthe prediction of late outcome events after acute coronary syndromes[J].J InternMed,2007,262(5):526-536.
[40]Yin WH,Chen JW,Jen HL,et al.The prognostic value of circulating soluble celladhesion molecules in patients with chronic congestive heart failure[J].Eur JHeart Fail,2003,5(4):507-516.
[41]Parissis JT,Karavidas A,Bistola V,et al. Effects of levosimendan onflow-mediated vasodilation and soluble adhesion molecules in patients withadvanced chronic heart failure[J].Atherosclerosis,2008,197(1):278-282.
[42]El-Menyar AA.Cytokines and myocardial dysfunction:State of the art[J].J CardFail,2008,14(1):61-74.
[43]Jug B,Salobir BG,Vene N,et al. Interleukin-6is a stronger prognostic predictorthan high-sensitive C-reactive protein in patients with chronic stable heartfailure[J].Heart Vessels,2009,24(4):271-276.
[44]Brown NJ.Aldosterone and vascular inflammation[J].Hypertension,2008,51(2):161-167.
[45]Yu XW,Chen Q,Kennedy RH,et al.Inhibition of sarcoplasmic reticular functionby chronic interleukin-6exposure via iNOS in adult ventricular myocytes[J].JPhysiol,2005,566(Pt2):327-340.
[46]Marcucci R,Gori AM,Giannotti F,et al.Markers of hypercoagulability andinflammation predict mortality in patients with heart failure[J].J ThrombHaemost,2006,4(5):1017-1022.
[47]Torre-Amione G.Immune activation in chronic heart failure[J].Am J Cardiol,2005,95(11A):3C-8C;discussion38C-40C.
[48]Kalantar-Zadeh K, Anker SD, Horwich TB, et al. Nutritional and anti-inflammatory interventions in chronic heart failure[J].Am J Cardiol,2008,101(11A):89E-103E.
[49]Shaw SM,Shah MK,Williams SG,et al.Immunological mechanisms ofpentoxifylline in chronic heart failure[J].Eur J Heart Fail,2009,11(2):113-118.
[50]Chrysohoou C,Pitsavos C,Barbetseas J,et al.Chronic systemic inflammationaccompanies impaired ventricular diastolic function,detected by Dopplerimaging,in patienta with newly diagnosed systolic heart failure (Hellenic HeartFailure Study)[J].Heart Vessels,2009,24(1):22-26.
[51]Dhingra S,Sharma AK,Arora RC,et al. IL-10attenuates TNF-alpha-induced NFkappa B pathway activation and cardiomyocyte apoptosis.tumor necrosisfactor[J].Circulation,2001,104(7):826-831.
[52]Sivasubramanian N,Coker ML,Kurrelmeyer KM,et al. Left ventricularremodeling in transgenic mice with cardiac restricted overexpression of tumornecrosis factor.Circulation,2001,104(7):826-831.
[53]葛德元,赵一举.心力衰竭的药物治疗[M].第2版.北京:科学技术文献出版社,2000:9210.
[54]Haisong Ju, Shufang Zhao, Davinder S Jassal, et al. Effect of AT1receptorblockade on cardiac collagen remodeling after myocardial infarction[J].Cardiovascular research,1997,35(2):223-232.
[55]Beltrami CA, Finato N, Rocco M, et al. Structural basis of end-stage failure inischemic cardiomyopathy in humans[J].Circulation,1994,89(1):151-163.
[56]Mayer SA, De Lemos JA, Murphy SA,et al. Comparison of B-type natriureticpeptide levls in patients with heart failure with versus without mitralregurgitation[J].Am J Cardiol,2004,93(8):1002-1006.
[57]Opie LH,Commerford PJ,Gersh BJ,et a1.Controversies in ventricularremodeling[J]. Lancet,2006;367(9507):356-367.
[58]Weber KT, Brilla CG, Janicki JS.Myocardial fibrosis:functional significance andregulatory factors[J]. Cardiovasc Res,1993,27(3):341-348.
[59]周欣,李玉明.心肌梗死后创伤修复与心室重塑[J].中华心血管病杂志,2004,32(4):375-378.
[60]Pfeffer MA, Braunwald E. Ventricular Remodeling after myocardial infarction.Experimental observations and clinical implications[J].Circulation,1990,81(4):1161-1172.
[61]Hutchins GM,Bulkley BH.Infarct expansion versus extension: two differentcomplications of acute myocardial infarction[J]. Am J Cardiol,1978,41(7):1127-1132.
[62]Dobaczewski M,Bujak M,Zymek P, et al. Extracellular matrix remodeling incanine and mouse myocardial infarcts[J]. Cell Tissue Res,2006,324(3):475-488.
[63]VannanMA, Taylor DJ. Ventricular remodeling after myocardial infarction [J]. BrHeart J,1992,68(3):257-259.
[64]赵鹏.急性心肌梗死与左室重构[J].国际内科学杂志,2007,34(1):17-20.
[65]LimMJ,KarolleBL,WoodJL,et al.Ischemic expansion during acute myocardialinfarction and reversal by coronary reperfusion[J].AmHeart J,1992,123(6):1456-1463.
[66]Weber KT. Cardiac interstitium in health and disease: the fibrillar collagennetwork[J]. J Am Coll Cardiol,1989,13(7):1637-1652.
[67]Willems IE, Havenith MG, De Mey JG, et al.The α-smooth muscle actin-positivecells in healing human myocardial scars[J]. Am J Pathol,1994;145(4):868-875.
[68]Gupta KB, Ratcliffe MB, Fallert MA,et al.Changes in the mechanical stiffness ofmyocardial tissue with aneurysm formation[J]. Circulation,1994,89(5):2315-2326.
[69]Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardialinfarction and cardiac remodeling[J]. Cardiovasc Res,2007,74(2):184–195.
[70]Stefan Frantz, Kai Hu, Anna Adamek, et al, Transforming growth factor betainhibition increases mortality and left ventricular dilation after myocardialinfarction[J]. Basic Res Cardiol.2008;103(5):485-492.
[71]Brilla CG. Renin-angiotensin-aldosterone system and myocardial fibrosis[J].Cardiovasc Res,2000,47(1):1-3.
[72]Pinto YM,Philipp T,Engler S, et al. Reduction in left ventricular messengerRNA for transforming growth factor β1attenuates left ventricular fibrosis andimproves survival without lowering blood pressure in the hypertensiveTGR(mRen2)27rat [J]. Hypertension,2000,36(5):747-754.
[73]Yu HCM, Burrell LM,Black MJ, et al. Salt induces myocardial and renal fibrosisin normotensive and hypertensive rats [J]. Circulation,1998,98(23):2621-2628.
[74]Ammarguellat F,Larouche L,Schiffrin E L.Myocardial fibrosis in DOCA-salthypertensive rats:effect of endothelin ET(A) receptor antagonism[J].Circulation,2001,103(2):319-324.
[75]Sun Y,Zhang J,Zhang JQ, et al.Local angiotensin II and transforming growthfactor-β1in renal fibrosis of rats [J]. Hypertension,2000,35(5):1078-1084.
[76]Kawano H, Do YS, Kawano Y, et al. Angiotensin II has multiple profibrothiceffects in human cardiac fibroblasts[J].Circulation,2000,101(10):1130-1137.
[77]Verrecchia F, Mauviel A.Transforming growth factor–beta signaling through theSmad pathway: role in extracellular matrix gene expression and regulation[J].JInvest Dermatol,2002,118(2):211-215.
[78]Katz A. The myocardium in congestive heart failure[J]. Am J Cardiol,1989,63:12A-16A.
[79]Mahon NG,O Roke,Codd M B,et a1.Hospital mortality of acute myocardialinfarction in the thrombolytic era[J].Heart,2005,81(3):478-482.
[80]Pfeffer JM.Progressive ventricular dilation in experimental myocardial infarctionand its attenuation by angiotesin converting enzyme inhibition[J].AmJ Cardiol,2006,68(14):17D-25D.
[81]Effect of enalapnl on survival in patients with reduced left ventricular ejectionfractions and congestive heart failure.The SOLVD Investigators[J].N Engl JMed,1991,325(5):293-302.
[82]Siragy H.Angiotensin II receptor blockers: review of the binding characteristics[J].Am J Cardiol,2004,84(10A):3S-8S.
[83]Kawaguchi H, Kitabatake A. Renin-angiotensin system in failing heart[J].J MolCell Cardiol,1995,27(1):201-209.
[84]王慧珍.急性心肌梗死后的心室重构及临床意义[J].新医学,2005,36:731-732.
[85]Sun Y,John Zhang JQ,Zhang J,et a1.Cardiac remodeling by fibrous tissue afterinfarction in rats[J].J Lab Med,2000,135(4):316-323.
[86]Mondry A,Swynqhedauw B.Bioligical adaption of the myocardium to chronicmechanical overload:Molecular determinant of the autonomic nervous system [J].Eur Heart J,1995,16SuppII:64-73.
[87]Starksen NF, Simpson PC, Bishopric N, et al. Cardiac myocyte hypertrophy isassociated with c-myc protooncogene expression [J]. Proc Nati Acad Sci USA,1986,83(21):8348-8350.
[88]Van Kats JP, Methot D, Paradis P,et al. Use of a biological peptide pump to studychronic peptide homone action in transgenic mice[J].Direct and indirect effects ofangiotensin II on the heart[J]. J Biol Chem,2001,276(47):44012-44017.
[89]Spyrou N,Rosen SD,Fath-Ordoubadi F,et a1.Myocardial beta-adrenoceptordensity one month after acute myocardial infarction predicts left ventdcularvolumes at six months[J].J Am Coll Cardil,2000,40(7):1216-1224.
[90]Kapadia SR, Oral H, Lee J, et a1. Hemodynamic regulation of tumor necrosisfactor-alpha gene and protein expression in adult feline myocardium[J].circ Res,1997,81(2):187-195.
[91]Kapadia s,Lee J,Torre AG, et a1. Tumor necrosis factor-alpha gene and proteinexpression in adult feIine myocardium after endotoxin adminstration[J].J CIinInvest,1995,96(2):1042-1052.
[92]Irwin MW,Mak S,Mann DL,et a1.Tissue expression and immunolocalization oftumour necrosis factor-alpha in post infarction-dysfunctional myocardium[J].circulation,1999,99(11):1492-1498.
[93]Gwechenberger M,Mendoza LH,Youker KA,et a1.cardiac myocytes produceinterleukin-6in cuhure and in viabIe border zone of reperfused infarctions[J].CircuIation,1999,99(4):546-551.
[94]Beg AA,Baltimore D.An essential role for NF-kappa B in preventingTNF-alpha-induced cell death[J].Science,1996,274(5288):782-784.
[95]Meldrum DR,Dinarello CA.Hydrogen peroxide induces tumor necrosis factoralphamediated cardiac injury by a p38mitogen activated protein“nase dependentmechanisms [J].Surgery,1998,124(2):29l-296．
[96]田斌.心肌细胞外基质的改变与心力衰竭[J].基础医学与临床,2000,20(3):214-219.
[97]晃银霞.卡维地洛对缺血性心脏病心力衰竭患者心室重塑和心功能的影响[J].中国综合临床,2004,20(4):303-305.
[98]Romanic AM,Burns-Kurtis CL,Gout B,et a1.Matrix etalloproteinase expressionin cardiac myocytes following myocardial infarction in the rabbit[J].LifeSci,2001,68(7):799-814.
[99]Lalu MM,Csonka C,Giricz Z.Preconditioning decreases ischemia/reperfusion-induced release and activation of matrix metallopmteinase-2[J].Biochem BiophysRes Commun,2002,296(4):937-941.
[100] CollenA,HanemaaijerR,LupuF,et al.Membrane-type matrix metellopro-teninase-mediated angiogenesis in a fibrin-collagen matrix[J].Blood,2003,101(5):1810-1817.
[101] Van Bilsen M,Smeets PJ,Gilde AJ,et al.Metabolic remodelling of the failingheart: the cardiac burn-out syndrome?[J].Cardiovasc Res,2004,61(2):218-226.
[102] Phillips D, Ten Hove M, Schneider JE, et al. Mice over-expressing themyocardial creatine transporter develop progressive heart failure and showdecreased glycolytic capacity[J]. J Mol Cell Cardiol,2010,48(4):582-590.
[103] Sharpe N.Ventricular remodeling following myocardial infarction[J].Am JCardiol1992,70(10):20C-26C.
[104] Siu SC,Nidorf SM,Galambos GS,et al. The effect of late patency of theinfarct-related coronary artery on left ventricular morphology and regionalfunction after thombo1ysis[J]. Am Heart J1992,124(2):265-272.
[105] Bonaduce D,Petretta M,Villari B,et al. Effects of late administration ofthssuetype plasminogen activator on left ventricular remodeling and functionafter myocardial infarction[J].J Am Cell Cardiol1990,16(7):1561-1568.
[106] Marino P,Zanolla L,Zardini P. Effect of streptokinase on left ventricularmodeling and function after myocardial infarction: the GISSI (Gruppo Italianoper lo Studio della Streptochinasi nell'Infarto Miocardico) Trial [J]. J Am CollCardiol1989,14(5):1149-1158.
[107] Emilien G, Maloteaux JM.Acute myocardial infarction:Role of β1adrenergicblockers[J]. Eur J Clin Pharmacol,1998,53(6):389-404.
[108] Roberts R, Rogers WJ, Mueller HS, et al. Immediate verse deferred beta-blockade following thrombolytic therapy in patients with acute myocardialinfarction[J]. Circulation,1991,83(2):422-437.
[109] Pole Wilson PA.ACE inhibitors and ARBs in chronic heart failure:Theestablished,the expected,and the pragmatic[J].Med Ciln North Am,2003,87(2):373-389.
[110] Cleland JGF. β-blockers for heart failure:Why,which,when and where[J].MedClin N Am,2003,87(4):329-331.
[111] Gullestad L,Aukrust P.Review of trials in chronic heart failure showingbroad-spectrum anti-inflammatory approaches[J].Am J Cardiol,2005,95(11A):17C-23C.
[112] Booth RE, Johnson JP,Stockand JD.Aldosterone[J]. Adv Physiol Educ,2002,26(1-4):8-20.
[113]程远植.醛固酮拮抗体螺内酯在慢性心力衰竭治疗中的作用机制和应用进展[J].中华心血管病杂志,2003,31(1):70.
[114] Poole-Wilson PA.ACE inhibitors and ARBs in chronic heart failure:Theestablished,the expected and the pragmatic[J].Med Clin N Am,2003,87(2):339-389.
[115] Coats ATS.Angiotensin type-1receptor blockers in heartfailure[J].ProgrCardiovasc Dis,2002,44(4):231-233.
[116] Patel R,Nagueh SH,Tsybouleva N,et al. Simvastatin induces regression ofcardiac hypertrophy and fibrosis and improves cardiac function a transgenicrabbit model of human hypertrophic cardimyopathy [J].Circulation,2001,104(3):317-324.
[117] Zhang JY,Cheng X,Liao YH,et a1.Simvastatin regulates myocardial cytokineexpression and improves ventricular remodeling in rats sfter acute myocmdlalinfarction[J].Cardiovasc Drugs Ther,2005,19(1):13-21.
[118] Node K,Fujita M,Kitakaze M,et a1.Short-term statin therapy improves Cardialfunction and symptoms in patients with idiopathic dilated cardiomyopathy[J].Circulation,2003,108:839-843.
[119]陈雨,朱晓华.糖尿病视网膜病变发病机制的研究进展[J].国际眼科杂志,2006,6(2):433-435.
[120]杨竞.糖尿病视网膜病变的成因和治疗[J].中国综合临床,2001,17(5):323-324.
[121] Cheng X,Lia YH,Li B,et a1.Atorvastatin reduces Th1development in patientswith acute myocardial infarction[J].Circulation,2004,110(17)Supplement III:696-697.
[122]盛红专,秦小同,黄宗勤.1,6-二磷酸果糖与辅酶Q10对大鼠阿霉素心脏毒性的保护作用比较[J].南通大学学报(医学版),2007,27(4):243-246.
[123]王忠全.1,6-二磷酸果糖的临床应用进展[J].中国药物应用与监测,2009,6(5):303-306.
[124]许晓晗,张维君.曲美他嗪在急性心肌梗死中的应用进展[J].中国急救复苏与灾害医学,2011,6(6):559-561.
[125] Lagadic-Gossmann D, Le Prigent K, Feuvray D. Effects of trimetazidine onpHi regulation in the rat isolated ventricular myocyte[J]. Br J Pharmacol.1996,117(5):831-838.
[126] Maupoil V, Rochette L, Tabard A, et al. Evaluation of free radical formationduring low-flow ischemia and reperfusion isolated rat heart[J].CardiovasDrugsTher,1990,4Suppl4:791-795.
[127] Guarniri C, Muscari C. Antioxy-radical properties of trimetazidine[J].ResComnmm Chem Pathol Pharmocol,1989,64(2):215-225.
[128] Vaillant F, Tsibiribi P, Bricca G, et al. Trimetazidine protective effect againstischemia-induced susceptibility to ventricular fibrillation in pigs[J].CardiovascDrugs Ther,2008,22(1):29-36.
[129]韩薇,杨树森,魏娜,等.心房颤动犬能量代谢变化及曲美他嗪干预研究[J],中华心血管病杂志,2008,36(6):556-559.
[130]毕福影.心力衰竭与改善心肌代谢药物治疗[J].中外健康文摘,2011,8(21):171.
[131]钱雪.辅酶Q10的药理与应用[J].食品与药品,2006,8(01):16-19.
[132]苏苹,郭庆亩,尹昭.心力衰竭的代谢与治疗[J].医学综述,2007,13:299-301.
[133] Carvajal K,Moreno-Sánchez R.Heart metabolic disturbances in cardiovasculardiseases[J].Arch Med Res,2003,34(2):89-99.
[134] Neubaner S.The failing heart--an engine out of fuel[J].N Engl J Med,2007,356(11):1140-1151.
[135] Ingwall JS, Poole-wilson PA, Coluccl WS,et al. ATP synthesis in the normaland failing heart[M]. Heart failure,1997.75-85.
[136] Stanley WC,Chandler MP.Energy metabolism in the normal and failingheart:potential for therapeutic interventions[J].Heart Fail.Rev.2002,7(2):15-130.
[137] Taegtmeyer H.Energy metabolism of the heart:form basic concepts to clinicalapplications[J].Curr Probl Cardiol,1994,19(2):59-113.
[138] Van der Vusse G J,Glatz JF,Stam HC,et al.Fatty acid homeostasis in thenormoxic and ischemic heart[J].Physiol Rev,1992,72(4):881-940.
[139] Ingwall JS,Weiss RG.Is the failure heart energy starved? On using chemicalenergy to support cardiac function[J].Circ Res,2004,95(2):135-145.
[140] Starling RC,Hammer DF,Altschuld RA.Human myocardial ATP content and invivo contractile function[J].Mol Cell Biochem,1998,180(1-2):171-177.
[141] Beer M, Seyfarth T, Sandstede J,et al. Absolute concentrations of high-energyphosphate metabolites in normal,hypertrophied,and failing human myocardiummeasured noninvasively with(31)P-SLOOP magnetic resonance spectroscopy[J].Am Coll Cardiol,2002,40(7):1267-1274.
[142] Liu J,Wang C,Murakami Y,et al.Mitochondrial ATPase and high-energyphosphates in failing hearts[J].Am J Physiol Heart Circ Physiol,2001,281(3):1319-H1326.
[143] Ten Hove M,Chan S,Lygate C,et al.Mechanisms of creatine depletion inchronically failing rat heart[J].J Mol Cell Cardiol,2005,38(2):309-313.
[144] Smith CS,Bottomley PA,Schulman SP,et a1.Altered creatine kinase adenosinetriphosphate kinetics in failing hypertrophied human myocardium[J].irculation,2006,114(11):1151-1158.
[145] Liao R,Nascimben L,Friedrich J,et al. Decreased energy reserve in an animalmodel of dilated cardiomypaththy.Relationship to contractile performance[J].Circ Res,1996,78(5):893-902.
[146] Neubauer S,Krahe T,Schindler R,et al.31P magnetic resonance spectroscopy indilated cardiomyopathy and coronary artery disease. Altered cardiac high-energymetabolism in heart failure[J].Circulation,1992,86(6):1810-1818.
[147] Neubauer S,Horn M,Cramer M, et al.Myocardial phosphocreatine-to-ATPratio is a predictor of mortality in patients with dilated cardiomyopathy[J].irculation,1997,96(7):2190-2196.
[148] Hu Q,Wang X,Lee J,et a1.Profound bioenergetic abnormalities in peri-infarctmyocardial regions[J].Am J Physiol Heart Circ Physiol,2006,291(2):648-H657.
[149] Maslov MY,Chacko VP,Stuber M,et a1.Altered high-energy phosphatemetabolism predicts contractile dysfunction and subsequent ventrieularremodeling in pressure-overload hypertrophym mice[J].Am J Physiol Heart CirePhysiol,2007,292(1):H387-391．
[150] Weiss RG,Gerstenblith G,Bottomley PA.ATP flux through creatine kinase in thenormal,stressed,and failing human heart[J].Proc Natl Acad Sci USA,005,02(3):808-813.
[151] Osorio JC, Stanley WC, Linke A, et al. Impaired myocardial fattyacid oxidationand reduced protein expression of retinoid X receptor-alpha in pacing-inducedheart failure[J]. Circulation,2002,106(5):606-612.
[152] Geltman EM, Smith JL, Beecher D, et al. Altered regional myocardialmetabolism in congestive cardiomyopathy detected by positron tomography[J].Am J Med,1983,74(5):773-785.
[153] Dulloo AG,Samec S.Seydoux J.Uncoupling protein3and fatty acidmetabolism[J]. Biochem Soc Trans,2001,29(Pt6):785-791.
[154] Lei B,Lionetti V,Young ME,et al.Paradoxical downregulation of the glucoseoxidation pathway despite enhanced flux in severe heart failure[J].J Mol CellCardiol,2004,36(4):567-576.
[155] Rosenblatt-Velin N, Montessuit C, Papageorgiou I, et al.Postinfarction heartfailure in rats is associated with upregulation of GLUT-1and downregulationof genes of fatty acid metabolism[J]. Cardiovasc Res,2001,52(3):407-416.
[156] Fuentes LD,Herrero P,Peterson LR,et al.Myocardial fatty acid metabolism:ndependent predictor of left ventricular mass in hypertensive heart diseaseJ].Hypertension,2003,41(1):83-87.
[157] Razeghi P,Young ME.Alcorn JL,et al.Metabolic gene expression in fetal andfailing human heart [J].Circulation,2001,104(24):2923-2931.
[158] Moe GW,Matin-Garcia J,Konig A,et a1.In vivo TNF-α inhibition amelioratescardiac mitochondrial dysfunction,oxidative stress,and apoptosis inexperimental heart failure[J].Am J Physiol Heart Circ Physiol,2004,287(4)：H1813-H1820.
[159] Ide T,Tsutsui H,Hayashidani S,et a1.Mitochondrial DNA damage anddysfunction associated with oxidative stress in failing hearts after myocardialinfarction[J].Circ Res,2001,88(5):529-535.
[160] Kuo WW,Chu CY,Wu CH,et al.The profile of cardiac cytochromec oxidaseCOX) xpression in an accelerated cardiac-hypertrophy model[J].J BiomedSci,2005,12(4):601-610.
[161] Kameyama T,Chen Z,Bell SP,et a1.Mechanoenergetic aherations during thetransition from cardiac hypertrophy to failure in Dahl salt-sensitive rats[J].irculation,1998,98(25):2919-2929.
[162] Das AM,Harris DA.Mitochondrial ATP synthase regulation in heart l:defects inhypertension are restored after treatment with captopril[J].Cardioscience,1992,3(4):227-232.
[163] Shertzer HG,Genter MB,Shen D,et a1.TCDD decreases ATP levels andincreases reactive oxygen production through changes in mitochondrialF(0)F(1)-ATP synthase and ubiquinone J].Toxicol Appl Pharmacol,2006,217(3):63-374.
[164] OBrien TX,Schuyler GT,Rackley MS,et a1.F1-ATP synthase beta-subunit andcytochrome c transcriptional regulation in right ventricular hemodynamicoverload and hypertrophically stimulated cardiocytes[J].J Mol CellCardiol,1999,31(1):167-178.
[165] Ning XH,Zhang J,Liu J,et a1.Signaling and expression for mitochondrialmembrane proteins during left ventficular remodelingn and contractile failureafter myocardial infarction[J].J Am Coll Cardiol,2000,36(1):282-287.
[166] Iijima T.Mitochondrial membrane potential and ischemic neuronal death[J].Neurosci Res,2006,55(3):234-243.
[167] Boss O,Hagen T,Lowell BB.Uncoupling proteins2and3: potential regulators ofmitochondrial energymetabolism[J]. Diabetes,2000,49(2):143-156
[168] Sharov VG,Todor A,Khanal S,et a1.Cyclosporine A attenuates mitochondrialpermeability transition and improves mitochondrial respiratory function ineardiomyocytes isolated from dogs with heart failure[J].J Mol CellCardiol,2007,42(1):150-158.
[169] Fukunaga Y,Itoh H,Hosoda K,et a1.Altered gene expression of uncouplingprotein-2and-3in stroke-prone spontaneously hypertensive rats[J].J Hypertens,2000,18(9):1233-1238．
[170] Takimoto E,Kass DA.Role of oxidative stress in cardiac hypertrophy andremodeling[J].Hypertension,2007,49(2):241-248.
[171] CollinA, Cassy S, Buyse J, et al.Potential involvement of mammalian and avianuncoupling proteins in the thermogenic effect of thyroid homones[J].DomestAnim Endocrino,2005,29(1):78-87.
[172] Guan L, GongD, TianN, et al.Uncoupling protein2involved in protection ofglucagons-like peptide2in small intestine with ischemia-reperfusion injury inmice[J].Dig Dis Sci,2005,50(3):554-560.
[173] Nicholls DG. Hamster brown-adipose-tissue mitochondria.purine nucleotidecontrol of the ion conductance of the inner membrane,the nature of thenucleotide binding site[J].Eur J Biochem,1976,62(2):223-228.
[174] Fleury C,Neverova M,Collins S,et al.Uncouling protein-2:a novel gene linked toobesity and hyperinsulinemia[J].Nat Genet,1997,15(3):269-272.
[175] Dalgaard LT,Pedersen O.Uncoupling proteins:functional characteristics and rolein the pathogenesis of obesity and type II diabetes[J].Diabetologia,2001,44(8):946-965.
[176] Jezek P, Urbánková E. Specific sequence of motifs of mitochondrial uncouplingproteins [J]. IUBMB Life,2000,49(1):63-70.
[177][177] eMl oualij B, Duyckaerts C, Lamotte-Brasseur J, et al. Phylogeneticclassification of the mitochondrial carrier family of Saccharomycescerevisiae[J].Yeast,1997,13(6):573-581.
[178] Pecqueur C,Cassard-Doulcier AM,Raimbautt S,et al.Functional organization ofthe human uncoupling protein-2gene,and juxtaposition to the uncouplingprotein-3gene[J].Biochem Biophys Res Commun,1999,255(1):40-46.
[179] Stuart JA,Harper JA,Brindle KM,et al.Physiological levels of mammalianuncoupling protein2do not uncouple yeast mitochondria[J]. J Biol Chem,2001,276(21):18633-18639.
[180] Chavin KD,Yang S,Lin HZ,et al.Obeslty induces expression of uncouplingprotein-2in hepatocytes and promotes liver ATP depletion[J].J Biol Chem,1999,274(9):5692-5700.
[181] Chan CB,De Leo D,Joseph JW,et al. Increased uncoupling protein-2levels inβ-cells associated with impaired glueose-stirnulated insulins secretionmechanism of action[J]. Diabetes,2001,50(6):1302-1310.
[182] Nagase I,Yoshida T,Saito M.Up-regulation of uncoupling proteins bybeta-adrenergic stimulation in L6myotubes[J].FEBS Lett,2001,494(3):175-180.
[183] Zhang CY,Baffy G,Perret P,et al.Uncoupling protein-2negatively regulatesinsulin secretion and is a major link between obesity,beta cell dysfunction,andtype2diabetes[J].Cell2001,105(6):745-755.
[184]顾景范,杜寿玢,查良锭,等.现代临床营养学[M].第1版．北京科学技术出版社,2003,20-33.
[185] St-Pierre J,Buckingham JA,Roebuck SJ,et a1.Topology of Superoxideproduction from Different Sites in the Mitochondrial Electron TransportChain[J].J Biol Chem,2002,277(47):44784-44790.
[186] Karim S,Echtay,Edith Winkler,Karina Frischmuth,et a1.Uncopling Proteins2and3are highly active H(+)transporters and highly nucleotide sensitive whenactivated by coenzyme Q(ubiquinone)[J].Proc Natl Acad Sci USA,2001,98(4):1416-1421.
[187] Pequeur C,Alves-Guerra MC,Gelly C,et a1.Uncoupling protein2, in vivodistribution,induction upon oxidative stress,and evidence for transitionalregulation[J].J Biol Chem,2001,276(12):8705-8712.
[188] Arsenijevic D,Onuma H,Pecquer C,et a1. Disruption of the uncouplingprotein-2gene in mice reveals a role in immunity and reactive oxygen speciesproduction[J].Nat Genet,2000,26(4):435-439.
[189] Jezek P,Hlavatá L.Mitochondria in homeostasis of reactive oxygen species incell,tissues, and organism[J].Int J Biochem Cell Biol,2005,37(12):2478-2503.
[190] Blane J, Alves-Guerra MC, Esposito B, et al. Protective role of uncouplingprotein2in atherosclerosis[J].Circulation,2003,107(3):388-390.
[191] Chan CB, MacDonald PE, Saleh MC, et a1. Overexpression of uncouplingprotein2inhibits glucose-stimulated insulin secretion from rat islets[J].Diabetes,1999,48(7):1482-1486．
[192] Kusmaul L,Hirst J.The mechanism of superoxide production by NADH:ubiquinone oxidoreductase(Complex I) from bovine heart mitochondria[J].ProcNatl Acad Sci USA,2006,103(20):7607-7612．
[193] Echtay KS,Roussel D,St-pierre J,et a1.Superoxide activates mitochondrialuncoupling proteins[J].Nature,2002,415(6867):96-99.
[194] Brand MD,Esteves TC.Physiological functions of the mitochondeial uncouplingprotiens UCP2and UCP3[J].Cell Metab,2005,2(2):85-93.
[195] Wulf Droge.Free radicals in the physiological control of cell function[J].Physiological Rev,2002,82(1):47-95.
[196] Christelle Merial,Anne Bouloumie,Veronique Trocheis,et a1. Nitric oxide-dependent downregulation of adipocyte UCP-2expression by tumor necrosisfactor-α[J].AM J Physiol Cell physiol,2000,279(4):C1100-C1106.
[197] Parish R, Petersen KF.Mitochondrial dysfunction and type2diabetes[J].CurrDiab Rep,2005,5(3):177-183.
[198] Dalgaard LT,Pedersen O.Uncoupling Proteins:functional charaeteristics and rolein the pathogenesis of obesity and type II diabetes[J].Diabetologia,2001,44(8):946-965.
[199] Matarrese P,Gambardella L,Caseone A,et a1.Mitochondrial membranehyperpolarizaation hijacks activated T lymphocytes toward the apoptotic-pronephenotype: homeostatic mechanisms of HIV protease inhibitors[J].J Immunol,2003,170(2):6006-6015.
[200] Kashemsant N,Chan CB.Impact of uncoupling protein-2overexpression onproinsulin processing[J].J Mol Endocrinol,2006,37(3):517-526.
[201] Yasuno K,Ando S,Misumi S,et a1.Synergisfic association of mitochondrialuncoupling protein(UCP)genes with schizophrenia[J].Am J Med Genet BNeuropsychiatr Genet,2007,144B(2):250-253.
[202] Esteves TC,Brand MD.The reactions catalysed by the mitochondrial uncouplingproteins UCP2and UCP3[J].Biochim Biophys Acta,2005,1709(1):35-44.
[203] Hong Y,Fink BD,Dillon JS,et a1.Effects of adenoviral overexpression of UCP-2and-3on mitochondrial respiration in insulinoma cells[J].Endocrinology,2001,142(1):249-256.
[204] Wang X,Axelsson J,Nordfom L,et a1.Changes in fat mass after initiation ofmaintenance dialysis is influenced by the uncoupling protein2exon8insertion/deletion polymorphism[J]. Nephrol Dial Transplant,2007,22(1):196-202.
[205] Park JY,Kim YM,Song HS,et a1.Oleic acid induces endothelin-1expressionthrough activation of protein kinase C and NF-kappa B[J].Biochem Biophys ResCommun,2003,303(3):891-895.
[206] Vogler S, Goedde R, Miterski B, et a1. Association of a common polymorphismin the promoter of UCP2with susceptibility to multiple sclerosis[J].J MolMed,2005,83(10):806-811.
[207] Kashemsant N,Chan CB.Impact of uncoupling protein-2overexpression onproinsulin processing[J].J Mol Endocfinol,2006,37(3):517-526.
[208] Medvedev AV,Snedden SK,Raimbault S,Ricquier D,Collins S.Transcriptionalregulation of the mouse uncoupling protein-2gene.Double E-box motif isrequired for peroxisome proliferator-activated receptor-gamma-dependentactivation[J].J Biol Chem,200l,276(14):10817-10823.
[209] Ogura R,Sugiyama M,Harmaki N,et a1.Electron Spin resonance studies on themechanism of adriamycin-induced heart mitochondrial damages[J].CancerRes,1991,51(13):3555-3558.
[210] Murray AJ, Anderson RE, Watson GC, et a1. Uncoupling proteins in humanheart[J]. Lancet,2004,364(9447):1786-1788.
[211] Murray AJ,Panagia M,Hauton D,et a1. Plasma free acids and peroxisomeproliferators-activated receptor alpha in the control of myocardial uncouplingprotein levels[J].Diabetes,2005,54(12):3496-3502.
[212] Lanni A,Mancini FP,SabatinoL,et a1.De novo expression of uncoupling protein3is associated to enhanced mitochondrial thioesterase-1expression and fattyacid metabo1ism in liver of fenofibrate-treated rats[J].FEBS Lett,2002,525(1-3):7-12.
[213] Reilly JM, Thompson MP. Dietary fatty acids up-regulate the expression ofUCP2in3T3-L1preadipocytes[J]. Biochem Biophys Res Commun,2000,277(3):541-545.
[214] Armstrong MB,Towle HC. Polyunsaturated fatty acids stimulate hepatic UCP-2expression via a PPARalpha-mediated pathway[J]. Am J Physiol EndocrinolMetab,2001,281(6):E1197-1204.
[215] Lentes KU,Tu N,Chen H,et a1.Genomic organization and mutational analysis ofthe human UCP2gene,a prime candidate gene for human obesity[J].J ReceptSignal Transduct Res,1999,19(1-4):229-244.
[216] Acín A, Rodriguez M, Rique H,et a1. Cloning and characterization of the5'flanking region of the human uncoupling protein3(UCP3) gene[J].BiochemBiophys Res Commun,1999,258(2):278-283.
[217] ThompsonMP, Kim D. Links between fatty acids and expression of UCP2andUCP3mRNAs[J]. FEBS Lett,2004,568(1-3):4-9.
[218] Fleury C,Sanchis D.The mitochondrial uncoupling protein-2:current status[J].IntJ Biochem Cell Biol,1999,31(11):1261-1278.
[219] ManciniFP, SabatinoL, ColantuoniVetal. Variants of uncoupling protein-2geneand obesity: interactionwith peroxisome proliferator-activated receptorgamma2[J].Clin Endocrinol (Oxf),2003,59(6):817-822.
[220] Sun x,Zemel MB. Role of uncoupling protein2(UCP2) expression and1alpha,25-dihydroxyvitamin D3in modulating adipocyte apoptosis[J].FASEBJ,2004,18(12):1430-1432.
[221] Hui Zhou, Jing Zhao, Xujia Zhang. Inhibition of uncoupling protein2by genipinreduces insulin-stimulated glucose uptake in3T3-L1adipocytes.Archives ofBiochemistry and Biophysics June.2009;88-93.
[222] Lanni A,De Felice M,Lombardi A,et al. Induction of UCP2mRNA by thyroidhormones in rat heart[J].FEBS Lett,1997,418(1-2):171-174.
[223] Masaki T,Yoshimatsu H,Kakuma T,et al.Enhanced expression of uncouplingprotein2gene in rat white adipose tissue and skeletal muscle following chronictreat ment with thyroid hormone[J]. FEBS Lett,1997,418(3):323-326.
[224] Van Der Lee KA,Willemsen PH,Van Der Vusse GJ,et al.Effects of fatty acids onuncoupling protein-2expression in the rat heart[J]. FASEB J,2000,14(3):495-502.
[225] Voci A,Demori I,Franzi AT,et al.Uncoupling protein2mRNA expression andrespiratory parameters in Kupffer cells isolated from euthyroid and hyperthyroidrat livers[J]. Eur J Endocrinol,2001,145(3):317-322.
[226] Scarpace PJ, Nicolson M, Matheny M, et al. UCP2, UCP3and leptin geneexpression: modulation by food restriction and leptin[J]. J Endocrinol,1998,159(2):349-357.
[227] Ceddia RB,William WN Jr,lima FB,et al.leptin stimulates uncoupling protein-2mRNA expression and Krebs cycle activity and inhibits lipid synthesis inisolated rat white adipocytes [J]. Eur J Biochem,2000,267(19):5952-5958.
[228] KatoH, OhueM, KatoK, et al. Mechanism of amelioration of insulin resistanceby beta3-adrenoceptor agonist AJ-9677in the KK-Ay/Ta diabetic obese mousemodel[J]. Diabetes,2001,50(1):113-122.
[229] Takemoto M, Node K, Nakagami H,et al. Statins as antioxidant therapy forpreventing cardiac myocyte hypertrophy[J]. J Clin Invest,2001,108(10):1429-1437.
[230] Pliquett RU, Cornish KG, Peuler JD,et al. Simvastatin normalizes autonomicneural control in experimental heart failure[J]. Circulation,2003,107(19):2493-2498.
[231]韩磊,叶平,刘永学,等.阿托伐他汀对老年大鼠心肌凋亡和过氧化物体增殖物激活型受体α蛋白表达的影响[J].中国动脉硬化杂志,2009,17(4):256-259.
[232] Faust JR, Brown MS, Goldstein JL. Synthesis of delta2-isopenteny l tRNAfrom mevalonate in cultured human fibroblasts[J].J Biol Chem,1980,255(14):6546-6548.
[233] Tao ZW, Huang YW, Xia Q, Xu QW. Combined effects of ramipril andangiotensin II receptor blocker TCV116on rat congestive heart failure aftermyocardial infarction[J]. Chin Med J (Engl),2005,118(2):146-154.
[234] Wu AH,Feng YJ.Biochemical differences between cTnT and cThI and theirsignificance of diagnosis of acute coronary syndyomes[J].Eur HeartJ,1998,19(Suppl N):N25-N29.
[235] MairJ, Morandell D, Genser N,et al. Euqivalent early sensitivities ofmyoglobin,creatine kinase MB mass,creatine kinase isoform ratios,and cardiactroponins I and T for acute myocardial infarction[J].Clin chem,1995,41(9):1266-1272.
[236] Chauhan D, Pandey P, Ogata A, et al. Cytochrome c-dependent and-independent induction of apoptosis in multiple myeloma cells[J]. J Biol Chem,1997,272(48):29995-29997.
[237] Juranek I, Bezek S. Controversy of free radical hypothesis: reactive oxygenspecies-cause or consequence of tissue injury?[J]. Gen Physiol Biophys,2005,24(3):263-278.
[238] Li JM, Gall NP, Grieve DJ, et al. Activation of NADPH oxidase duringprogression of cardiac hypertrophy to failure[J]. Hypertension,2002,40(4):477-484.
[239] Seshiah PN, Weber DS, Rocic P, et al. Angiotensin II stimulation of NAD(P)Hoxidase activity:upstream mediators[J]. Circ Res,2002,91(5):406-413.
[240] Rikitake Y, Kawashima S, Takeshita S, et al. Anti-oxidative property offluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention ofatherosclerosis in cholesterol-fed rabbits[J]. Atherosclerosis,2001,154(1):87-96.
[241] Wassmann S, Laufs U, Baumer AT, et al. Inhibition of geranylgeranylationreduces angiotensin II-mediated free radical production in vascular smoothmuscle cells: involvement of angiotensin AT1receptor expression and Rac1GTPase[J]. Mol Pharmacol,2001,59(3):646-654.
[242] Molloy CJ,Taylor DS,Weber H.Angiotensin II stimulation of rapid proteintyrosine phosphorylation and protein kinase activation in rat aortic smoothmuscle cells[J].J Biol Chem,1993,268(10):7338-7345.
[243] Eguchi S, Matsumoto T, Motley ED, et al. Identification of an essentialsignaling cascade for mitogen-activated protein kinase activation by angiotensinII in cultured rat vascular smooth muscle cells. Possible requirement ofGq-mediated p21ras activation coupled to a Ca2+/calmodulin-sensitive tyrosinekinase[J].J Biol Chem,1996,271(24):14169-14175.
[244] Sadoshima J, Izumo S. The heterotrimeric G q protein-coupled angiotensin IIreceptor activates p21ras via the tyrosine kinase-Shc-Grb2-Sos pathway incardiac myocytes[J].EMBO J,1996,15(4):775-787.
[245] Davis RJ. The mitogen-activated protein kinase signal transduction pathway[J].JBiol Chem,1993;268(20):14553-14556.
[2] McMurray JJ,Pfeffer MA.Heart failure[J].Lancet,2005,365(9474):1877-1889.
[3]戴闺柱.2005年美国慢性收缩性心力衰竭治疗指南浅析[J].中华心血管病志,2005,3(12):1065-1066.
[4]张义红.神经内分泌激活与心肌细胞凋亡在心力衰蝎发生发展中的作用及机制[J].心血管病学进展,2001,22:50-53.
[5]史亚非.充血性心力衰竭肾上腺素途径的变化及其临床意义[J].国外医学―心血管分册,1995,326-330.
[6] Antos CL, Frey N, Marx SO, et a1. Dilated cardiomyopathy and sudden deathresulting from constitutive activation of protein kinase A[J]. Circ Res,2001,89(11):997-1004.
[7]崔希忠.交感神经神经系统兴奋在充血性心力衰竭中的临床意义[J].国外医学―心血管分册,1996,23:314-316.
[8] Serneri GG,Boddi M,Cecioni I,et al.Cardiac angiotensin II formation in theclinical course of heart failure and its relationship with left ventricularfunction[J].Circ Res,2001,88(9):961-968.
[9] Miserey S,Clauser E.Angiotensin II receptor:classification,structure and signaltransduction [J].Therapie,1998,53(3):205-11.
[10]Schultz JE,Witt SA,Glascock BJ,et al.TGF-β1mediates the hypertrophiccardiomyocyte growth induced by angiotensin II[J].J Clin Invest,2002,109(6):787-96.
[11]Lijnen P,Petrov V.Renin-angiotensin system,hypertrophy and gene exoression incardiac myocytes[J].J Mol Cell Cardiol,1999,31(5):949-70.
[12]Kawano H, Do YS, Kawano Y, et al.Angiotensin II has multiple prebrothiceffects in human cardiac fibroblasts [J].Circulation,2000,1(10):1130-1137.
[13]ZhangD,GaussinV,SchneiderM D,et al.TAK1is activated in the myocardiumafter pressure overload and is sufficient to provoke heart failure in transgenicmice[J].Nat Med,2000,6(5):556-563.
[14]Mondry A,Swynghedauw B.Bioligical adaption of the myocardium to chronicmechanical overload: Molecular determinant of the autonomic nervous system [J].Eur Heart J,1995,16:64-73.
[15]Starksen NF,Simpson PC,Bishopric N, et al. Cardiac myocyte hypertrophy isassociated with c-myc protooncogene expression [J]. Proc Nati Acad SciUSA,1986,83(21):8348-8350.
[16]Zannad F.Aldostorone and heart failure[J]. Eur heart J,1995,16(suppl N):98-102.
[17]Mc Mahon EG.Recent studies with eplerenone, a novel selective aldosteronereceptor antagonist[J]. Curr Opin Pharmacol,2001,1(2):190-196.
[18]Weber KT,Brilla CG.Pathological hypertrophy and cardiac interstitium: fibrosisand renin-angiotensin-aldosterone system[J].Circulation,1991,83(6):1849-1865.
[19]Nishimura H. Comparative endocrinology of renin and angiotensin[J].Adv ExpMed Biol,1980,130,29-77.
[20]Schohn DC,Jahn HA, Pelletier BC. Dose-related cardiovascular effects ofspironolactone[J]. Am J cardiol,1993,719(3):40A-45A.
[21]Sies H, Brigelius R, Wefers H, et al.Cellular redox changes and response todrugs and toxic agents[J]. Fundam Appl Toxicol,1983,3(4):200-208.
[22]Dominik N Muller,Ralf Dechend,Eero M.A. Mervaala, et al. NF-κB Inhibitionameliorates angiotensin II-induced inflammatory damage in rats[J]. Hypertension,2000,35(1Pt2):193-201.
[23]Poderoso JJ, Carreras MC,Lisdero C, et al. Nitric oxide inhibits electron transferand increases superoxide radical production in rat heart mitochondria andsubmitochondrial particles[J].Arch Biochem Biophys,1996,328(1):85-92.
[24]Han YJ, Kwon YG, ChunghHT, et al. Antioxidant enzymes suppress nitric oxideproduction through the inhibition of NF-κB activation: role of H2O2and nitricoxide in inducible nitric oxide synthase expression in macrophages[J]. NitricOxide,2001,59(5):504-513.
[25]Forman HJ, Torres M, Fukuto J. Redox signaling[J]. Mol Cell Biochem,2002,234-235(1-2):49-62.
[26]Ungvari Z, Orosz Z, Labinskyy N, et al. Increased mitochondrial H2O2production promotes endothelial NF-κB activation in aged rat arteries[J]. Am JPhysiol Heart Circ Physiol,2007,293(4): H37-47.
[27]Li JM, Gall NP, Grieve DJ, et al. Activation of NADPH oxidase duringprogression of cardiac hypertrophy to failure[J]. Hypertension,2002,40(4):477-484.
[28]Higuchi Y, Otsu K, Nishida K, et al. Involvement of reactive oxygen species-mediated NF-κappa B activation in TNF-alpha-induced cardiomyocytehypertrophy[J]. J Mol Cell Cardiol,2002,34(2):233-240.
[29]Xiao L, Pimentel DR, Wang J, et al. Role of reactive oxygen species andNAD(P)H oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiacmyocytes[J]. Am J Physiol Cell Physiol,2002,282(4):926-934.
[30]游琪,蔡久英.氧化应激与心肌损伤的研究进展[J].临床荟萃,2005,20(19):1127-1129.
[31]Pimentel DR,Amin JK,Xiso L, et al.Reactive oxygen species mediateamplitudedependent hypertrophic and apoptotic responses to mechanical stretchin cardiac myocytes[J]. Ciro Res,2001,89(5):453-460.
[32]Li M, Georgakopoulos D, Lu G, et al. p38MAP Kinase mediates inflammatorycytokine induction in cardiomyocytes and extracellular matrix remodeling inheart[J]. Circulation,2005,111(19):2494-2502.
[33]Gill C, Mestril R, Samali A. Losing heart:the role of apoptosis in heartdiseasea-a novel therapeutic target?[J].FASEB J,2002,16(2):135-146.
[34]Ruixinq Y,Dezhai Y,Jiaquan L.Effects of cardiotrophin-1on hemodynamics andcardiomyocyte apoptosis in rats with acute myocardial infarction[J].J MedInvest,2004,51(1-2):29-37.
[35]SperrWR,Bankl HC,Mundiqler G,et al.The human cardiac mast cell:localization,isolation,phenotype,and functional characterization[J]. Blood,1994,84(11):3876-3884.
[36]Hara M,Matsumori A,Ono K,etal.Mast cells cause apoptosis of cardiomyocytesand proliferation of other intramyocardial cells in vitro[J].Circulation,1999,100(13):1443-1449
[37]Thorburn A.Death receptor-induced cell killing[J].Cell Signal,2004,170(6):3118-3124.
[38]Liao X,Wang X,GU Y,et al. Involvement of death receptor signaling inmechanical stretch-induced cardiomyocyte apoptosis[J].Life Sci,2005,77(2):160-
[39]Hartford M,Wiklund O,Mattsson Hulten L, et al.C-reactive protein,interleukin-6,secretory phospholipase A2group II A and intercellular adhesion molecule-1inthe prediction of late outcome events after acute coronary syndromes[J].J InternMed,2007,262(5):526-536.
[40]Yin WH,Chen JW,Jen HL,et al.The prognostic value of circulating soluble celladhesion molecules in patients with chronic congestive heart failure[J].Eur JHeart Fail,2003,5(4):507-516.
[41]Parissis JT,Karavidas A,Bistola V,et al. Effects of levosimendan onflow-mediated vasodilation and soluble adhesion molecules in patients withadvanced chronic heart failure[J].Atherosclerosis,2008,197(1):278-282.
[42]El-Menyar AA.Cytokines and myocardial dysfunction:State of the art[J].J CardFail,2008,14(1):61-74.
[43]Jug B,Salobir BG,Vene N,et al. Interleukin-6is a stronger prognostic predictorthan high-sensitive C-reactive protein in patients with chronic stable heartfailure[J].Heart Vessels,2009,24(4):271-276.
[44]Brown NJ.Aldosterone and vascular inflammation[J].Hypertension,2008,51(2):161-167.
[45]Yu XW,Chen Q,Kennedy RH,et al.Inhibition of sarcoplasmic reticular functionby chronic interleukin-6exposure via iNOS in adult ventricular myocytes[J].JPhysiol,2005,566(Pt2):327-340.
[46]Marcucci R,Gori AM,Giannotti F,et al.Markers of hypercoagulability andinflammation predict mortality in patients with heart failure[J].J ThrombHaemost,2006,4(5):1017-1022.
[47]Torre-Amione G.Immune activation in chronic heart failure[J].Am J Cardiol,2005,95(11A):3C-8C;discussion38C-40C.
[48]Kalantar-Zadeh K, Anker SD, Horwich TB, et al. Nutritional and anti-inflammatory interventions in chronic heart failure[J].Am J Cardiol,2008,101(11A):89E-103E.
[49]Shaw SM,Shah MK,Williams SG,et al.Immunological mechanisms ofpentoxifylline in chronic heart failure[J].Eur J Heart Fail,2009,11(2):113-118.
[50]Chrysohoou C,Pitsavos C,Barbetseas J,et al.Chronic systemic inflammationaccompanies impaired ventricular diastolic function,detected by Dopplerimaging,in patienta with newly diagnosed systolic heart failure (Hellenic HeartFailure Study)[J].Heart Vessels,2009,24(1):22-26.
[51]Dhingra S,Sharma AK,Arora RC,et al. IL-10attenuates TNF-alpha-induced NFkappa B pathway activation and cardiomyocyte apoptosis.tumor necrosisfactor[J].Circulation,2001,104(7):826-831.
[52]Sivasubramanian N,Coker ML,Kurrelmeyer KM,et al. Left ventricularremodeling in transgenic mice with cardiac restricted overexpression of tumornecrosis factor.Circulation,2001,104(7):826-831.
[53]葛德元,赵一举.心力衰竭的药物治疗[M].第2版.北京:科学技术文献出版社,2000:9210.
[54]Haisong Ju, Shufang Zhao, Davinder S Jassal, et al. Effect of AT1receptorblockade on cardiac collagen remodeling after myocardial infarction[J].Cardiovascular research,1997,35(2):223-232.
[55]Beltrami CA, Finato N, Rocco M, et al. Structural basis of end-stage failure inischemic cardiomyopathy in humans[J].Circulation,1994,89(1):151-163.
[56]Mayer SA, De Lemos JA, Murphy SA,et al. Comparison of B-type natriureticpeptide levls in patients with heart failure with versus without mitralregurgitation[J].Am J Cardiol,2004,93(8):1002-1006.
[57]Opie LH,Commerford PJ,Gersh BJ,et a1.Controversies in ventricularremodeling[J]. Lancet,2006;367(9507):356-367.
[58]Weber KT, Brilla CG, Janicki JS.Myocardial fibrosis:functional significance andregulatory factors[J]. Cardiovasc Res,1993,27(3):341-348.
[59]周欣,李玉明.心肌梗死后创伤修复与心室重塑[J].中华心血管病杂志,2004,32(4):375-378.
[60]Pfeffer MA, Braunwald E. Ventricular Remodeling after myocardial infarction.Experimental observations and clinical implications[J].Circulation,1990,81(4):1161-1172.
[61]Hutchins GM,Bulkley BH.Infarct expansion versus extension: two differentcomplications of acute myocardial infarction[J]. Am J Cardiol,1978,41(7):1127-1132.
[62]Dobaczewski M,Bujak M,Zymek P, et al. Extracellular matrix remodeling incanine and mouse myocardial infarcts[J]. Cell Tissue Res,2006,324(3):475-488.
[63]VannanMA, Taylor DJ. Ventricular remodeling after myocardial infarction [J]. BrHeart J,1992,68(3):257-259.
[64]赵鹏.急性心肌梗死与左室重构[J].国际内科学杂志,2007,34(1):17-20.
[65]LimMJ,KarolleBL,WoodJL,et al.Ischemic expansion during acute myocardialinfarction and reversal by coronary reperfusion[J].AmHeart J,1992,123(6):1456-1463.
[66]Weber KT. Cardiac interstitium in health and disease: the fibrillar collagennetwork[J]. J Am Coll Cardiol,1989,13(7):1637-1652.
[67]Willems IE, Havenith MG, De Mey JG, et al.The α-smooth muscle actin-positivecells in healing human myocardial scars[J]. Am J Pathol,1994;145(4):868-875.
[68]Gupta KB, Ratcliffe MB, Fallert MA,et al.Changes in the mechanical stiffness ofmyocardial tissue with aneurysm formation[J]. Circulation,1994,89(5):2315-2326.
[69]Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardialinfarction and cardiac remodeling[J]. Cardiovasc Res,2007,74(2):184–195.
[70]Stefan Frantz, Kai Hu, Anna Adamek, et al, Transforming growth factor betainhibition increases mortality and left ventricular dilation after myocardialinfarction[J]. Basic Res Cardiol.2008;103(5):485-492.
[71]Brilla CG. Renin-angiotensin-aldosterone system and myocardial fibrosis[J].Cardiovasc Res,2000,47(1):1-3.
[72]Pinto YM,Philipp T,Engler S, et al. Reduction in left ventricular messengerRNA for transforming growth factor β1attenuates left ventricular fibrosis andimproves survival without lowering blood pressure in the hypertensiveTGR(mRen2)27rat [J]. Hypertension,2000,36(5):747-754.
[73]Yu HCM, Burrell LM,Black MJ, et al. Salt induces myocardial and renal fibrosisin normotensive and hypertensive rats [J]. Circulation,1998,98(23):2621-2628.
[74]Ammarguellat F,Larouche L,Schiffrin E L.Myocardial fibrosis in DOCA-salthypertensive rats:effect of endothelin ET(A) receptor antagonism[J].Circulation,2001,103(2):319-324.
[75]Sun Y,Zhang J,Zhang JQ, et al.Local angiotensin II and transforming growthfactor-β1in renal fibrosis of rats [J]. Hypertension,2000,35(5):1078-1084.
[76]Kawano H, Do YS, Kawano Y, et al. Angiotensin II has multiple profibrothiceffects in human cardiac fibroblasts[J].Circulation,2000,101(10):1130-1137.
[77]Verrecchia F, Mauviel A.Transforming growth factor–beta signaling through theSmad pathway: role in extracellular matrix gene expression and regulation[J].JInvest Dermatol,2002,118(2):211-215.
[78]Katz A. The myocardium in congestive heart failure[J]. Am J Cardiol,1989,63:12A-16A.
[79]Mahon NG,O Roke,Codd M B,et a1.Hospital mortality of acute myocardialinfarction in the thrombolytic era[J].Heart,2005,81(3):478-482.
[80]Pfeffer JM.Progressive ventricular dilation in experimental myocardial infarctionand its attenuation by angiotesin converting enzyme inhibition[J].AmJ Cardiol,2006,68(14):17D-25D.
[81]Effect of enalapnl on survival in patients with reduced left ventricular ejectionfractions and congestive heart failure.The SOLVD Investigators[J].N Engl JMed,1991,325(5):293-302.
[82]Siragy H.Angiotensin II receptor blockers: review of the binding characteristics[J].Am J Cardiol,2004,84(10A):3S-8S.
[83]Kawaguchi H, Kitabatake A. Renin-angiotensin system in failing heart[J].J MolCell Cardiol,1995,27(1):201-209.
[84]王慧珍.急性心肌梗死后的心室重构及临床意义[J].新医学,2005,36:731-732.
[85]Sun Y,John Zhang JQ,Zhang J,et a1.Cardiac remodeling by fibrous tissue afterinfarction in rats[J].J Lab Med,2000,135(4):316-323.
[86]Mondry A,Swynqhedauw B.Bioligical adaption of the myocardium to chronicmechanical overload:Molecular determinant of the autonomic nervous system [J].Eur Heart J,1995,16SuppII:64-73.
[87]Starksen NF, Simpson PC, Bishopric N, et al. Cardiac myocyte hypertrophy isassociated with c-myc protooncogene expression [J]. Proc Nati Acad Sci USA,1986,83(21):8348-8350.
[88]Van Kats JP, Methot D, Paradis P,et al. Use of a biological peptide pump to studychronic peptide homone action in transgenic mice[J].Direct and indirect effects ofangiotensin II on the heart[J]. J Biol Chem,2001,276(47):44012-44017.
[89]Spyrou N,Rosen SD,Fath-Ordoubadi F,et a1.Myocardial beta-adrenoceptordensity one month after acute myocardial infarction predicts left ventdcularvolumes at six months[J].J Am Coll Cardil,2000,40(7):1216-1224.
[90]Kapadia SR, Oral H, Lee J, et a1. Hemodynamic regulation of tumor necrosisfactor-alpha gene and protein expression in adult feline myocardium[J].circ Res,1997,81(2):187-195.
[91]Kapadia s,Lee J,Torre AG, et a1. Tumor necrosis factor-alpha gene and proteinexpression in adult feIine myocardium after endotoxin adminstration[J].J CIinInvest,1995,96(2):1042-1052.
[92]Irwin MW,Mak S,Mann DL,et a1.Tissue expression and immunolocalization oftumour necrosis factor-alpha in post infarction-dysfunctional myocardium[J].circulation,1999,99(11):1492-1498.
[93]Gwechenberger M,Mendoza LH,Youker KA,et a1.cardiac myocytes produceinterleukin-6in cuhure and in viabIe border zone of reperfused infarctions[J].CircuIation,1999,99(4):546-551.
[94]Beg AA,Baltimore D.An essential role for NF-kappa B in preventingTNF-alpha-induced cell death[J].Science,1996,274(5288):782-784.
[95]Meldrum DR,Dinarello CA.Hydrogen peroxide induces tumor necrosis factoralphamediated cardiac injury by a p38mitogen activated protein“nase dependentmechanisms [J].Surgery,1998,124(2):29l-296．
[96]田斌.心肌细胞外基质的改变与心力衰竭[J].基础医学与临床,2000,20(3):214-219.
[97]晃银霞.卡维地洛对缺血性心脏病心力衰竭患者心室重塑和心功能的影响[J].中国综合临床,2004,20(4):303-305.
[98]Romanic AM,Burns-Kurtis CL,Gout B,et a1.Matrix etalloproteinase expressionin cardiac myocytes following myocardial infarction in the rabbit[J].LifeSci,2001,68(7):799-814.
[99]Lalu MM,Csonka C,Giricz Z.Preconditioning decreases ischemia/reperfusion-induced release and activation of matrix metallopmteinase-2[J].Biochem BiophysRes Commun,2002,296(4):937-941.
[100] CollenA,HanemaaijerR,LupuF,et al.Membrane-type matrix metellopro-teninase-mediated angiogenesis in a fibrin-collagen matrix[J].Blood,2003,101(5):1810-1817.
[101] Van Bilsen M,Smeets PJ,Gilde AJ,et al.Metabolic remodelling of the failingheart: the cardiac burn-out syndrome?[J].Cardiovasc Res,2004,61(2):218-226.
[102] Phillips D, Ten Hove M, Schneider JE, et al. Mice over-expressing themyocardial creatine transporter develop progressive heart failure and showdecreased glycolytic capacity[J]. J Mol Cell Cardiol,2010,48(4):582-590.
[103] Sharpe N.Ventricular remodeling following myocardial infarction[J].Am JCardiol1992,70(10):20C-26C.
[104] Siu SC,Nidorf SM,Galambos GS,et al. The effect of late patency of theinfarct-related coronary artery on left ventricular morphology and regionalfunction after thombo1ysis[J]. Am Heart J1992,124(2):265-272.
[105] Bonaduce D,Petretta M,Villari B,et al. Effects of late administration ofthssuetype plasminogen activator on left ventricular remodeling and functionafter myocardial infarction[J].J Am Cell Cardiol1990,16(7):1561-1568.
[106] Marino P,Zanolla L,Zardini P. Effect of streptokinase on left ventricularmodeling and function after myocardial infarction: the GISSI (Gruppo Italianoper lo Studio della Streptochinasi nell'Infarto Miocardico) Trial [J]. J Am CollCardiol1989,14(5):1149-1158.
[107] Emilien G, Maloteaux JM.Acute myocardial infarction:Role of β1adrenergicblockers[J]. Eur J Clin Pharmacol,1998,53(6):389-404.
[108] Roberts R, Rogers WJ, Mueller HS, et al. Immediate verse deferred beta-blockade following thrombolytic therapy in patients with acute myocardialinfarction[J]. Circulation,1991,83(2):422-437.
[109] Pole Wilson PA.ACE inhibitors and ARBs in chronic heart failure:Theestablished,the expected,and the pragmatic[J].Med Ciln North Am,2003,87(2):373-389.
[110] Cleland JGF. β-blockers for heart failure:Why,which,when and where[J].MedClin N Am,2003,87(4):329-331.
[111] Gullestad L,Aukrust P.Review of trials in chronic heart failure showingbroad-spectrum anti-inflammatory approaches[J].Am J Cardiol,2005,95(11A):17C-23C.
[112] Booth RE, Johnson JP,Stockand JD.Aldosterone[J]. Adv Physiol Educ,2002,26(1-4):8-20.
[113]程远植.醛固酮拮抗体螺内酯在慢性心力衰竭治疗中的作用机制和应用进展[J].中华心血管病杂志,2003,31(1):70.
[114] Poole-Wilson PA.ACE inhibitors and ARBs in chronic heart failure:Theestablished,the expected and the pragmatic[J].Med Clin N Am,2003,87(2):339-389.
[115] Coats ATS.Angiotensin type-1receptor blockers in heartfailure[J].ProgrCardiovasc Dis,2002,44(4):231-233.
[116] Patel R,Nagueh SH,Tsybouleva N,et al. Simvastatin induces regression ofcardiac hypertrophy and fibrosis and improves cardiac function a transgenicrabbit model of human hypertrophic cardimyopathy [J].Circulation,2001,104(3):317-324.
[117] Zhang JY,Cheng X,Liao YH,et a1.Simvastatin regulates myocardial cytokineexpression and improves ventricular remodeling in rats sfter acute myocmdlalinfarction[J].Cardiovasc Drugs Ther,2005,19(1):13-21.
[118] Node K,Fujita M,Kitakaze M,et a1.Short-term statin therapy improves Cardialfunction and symptoms in patients with idiopathic dilated cardiomyopathy[J].Circulation,2003,108:839-843.
[119]陈雨,朱晓华.糖尿病视网膜病变发病机制的研究进展[J].国际眼科杂志,2006,6(2):433-435.
[120]杨竞.糖尿病视网膜病变的成因和治疗[J].中国综合临床,2001,17(5):323-324.
[121] Cheng X,Lia YH,Li B,et a1.Atorvastatin reduces Th1development in patientswith acute myocardial infarction[J].Circulation,2004,110(17)Supplement III:696-697.
[122]盛红专,秦小同,黄宗勤.1,6-二磷酸果糖与辅酶Q10对大鼠阿霉素心脏毒性的保护作用比较[J].南通大学学报(医学版),2007,27(4):243-246.
[123]王忠全.1,6-二磷酸果糖的临床应用进展[J].中国药物应用与监测,2009,6(5):303-306.
[124]许晓晗,张维君.曲美他嗪在急性心肌梗死中的应用进展[J].中国急救复苏与灾害医学,2011,6(6):559-561.
[125] Lagadic-Gossmann D, Le Prigent K, Feuvray D. Effects of trimetazidine onpHi regulation in the rat isolated ventricular myocyte[J]. Br J Pharmacol.1996,117(5):831-838.
[126] Maupoil V, Rochette L, Tabard A, et al. Evaluation of free radical formationduring low-flow ischemia and reperfusion isolated rat heart[J].CardiovasDrugsTher,1990,4Suppl4:791-795.
[127] Guarniri C, Muscari C. Antioxy-radical properties of trimetazidine[J].ResComnmm Chem Pathol Pharmocol,1989,64(2):215-225.
[128] Vaillant F, Tsibiribi P, Bricca G, et al. Trimetazidine protective effect againstischemia-induced susceptibility to ventricular fibrillation in pigs[J].CardiovascDrugs Ther,2008,22(1):29-36.
[129]韩薇,杨树森,魏娜,等.心房颤动犬能量代谢变化及曲美他嗪干预研究[J],中华心血管病杂志,2008,36(6):556-559.
[130]毕福影.心力衰竭与改善心肌代谢药物治疗[J].中外健康文摘,2011,8(21):171.
[131]钱雪.辅酶Q10的药理与应用[J].食品与药品,2006,8(01):16-19.
[132]苏苹,郭庆亩,尹昭.心力衰竭的代谢与治疗[J].医学综述,2007,13:299-301.
[133] Carvajal K,Moreno-Sánchez R.Heart metabolic disturbances in cardiovasculardiseases[J].Arch Med Res,2003,34(2):89-99.
[134] Neubaner S.The failing heart--an engine out of fuel[J].N Engl J Med,2007,356(11):1140-1151.
[135] Ingwall JS, Poole-wilson PA, Coluccl WS,et al. ATP synthesis in the normaland failing heart[M]. Heart failure,1997.75-85.
[136] Stanley WC,Chandler MP.Energy metabolism in the normal and failingheart:potential for therapeutic interventions[J].Heart Fail.Rev.2002,7(2):15-130.
[137] Taegtmeyer H.Energy metabolism of the heart:form basic concepts to clinicalapplications[J].Curr Probl Cardiol,1994,19(2):59-113.
[138] Van der Vusse G J,Glatz JF,Stam HC,et al.Fatty acid homeostasis in thenormoxic and ischemic heart[J].Physiol Rev,1992,72(4):881-940.
[139] Ingwall JS,Weiss RG.Is the failure heart energy starved? On using chemicalenergy to support cardiac function[J].Circ Res,2004,95(2):135-145.
[140] Starling RC,Hammer DF,Altschuld RA.Human myocardial ATP content and invivo contractile function[J].Mol Cell Biochem,1998,180(1-2):171-177.
[141] Beer M, Seyfarth T, Sandstede J,et al. Absolute concentrations of high-energyphosphate metabolites in normal,hypertrophied,and failing human myocardiummeasured noninvasively with(31)P-SLOOP magnetic resonance spectroscopy[J].Am Coll Cardiol,2002,40(7):1267-1274.
[142] Liu J,Wang C,Murakami Y,et al.Mitochondrial ATPase and high-energyphosphates in failing hearts[J].Am J Physiol Heart Circ Physiol,2001,281(3):1319-H1326.
[143] Ten Hove M,Chan S,Lygate C,et al.Mechanisms of creatine depletion inchronically failing rat heart[J].J Mol Cell Cardiol,2005,38(2):309-313.
[144] Smith CS,Bottomley PA,Schulman SP,et a1.Altered creatine kinase adenosinetriphosphate kinetics in failing hypertrophied human myocardium[J].irculation,2006,114(11):1151-1158.
[145] Liao R,Nascimben L,Friedrich J,et al. Decreased energy reserve in an animalmodel of dilated cardiomypaththy.Relationship to contractile performance[J].Circ Res,1996,78(5):893-902.
[146] Neubauer S,Krahe T,Schindler R,et al.31P magnetic resonance spectroscopy indilated cardiomyopathy and coronary artery disease. Altered cardiac high-energymetabolism in heart failure[J].Circulation,1992,86(6):1810-1818.
[147] Neubauer S,Horn M,Cramer M, et al.Myocardial phosphocreatine-to-ATPratio is a predictor of mortality in patients with dilated cardiomyopathy[J].irculation,1997,96(7):2190-2196.
[148] Hu Q,Wang X,Lee J,et a1.Profound bioenergetic abnormalities in peri-infarctmyocardial regions[J].Am J Physiol Heart Circ Physiol,2006,291(2):648-H657.
[149] Maslov MY,Chacko VP,Stuber M,et a1.Altered high-energy phosphatemetabolism predicts contractile dysfunction and subsequent ventrieularremodeling in pressure-overload hypertrophym mice[J].Am J Physiol Heart CirePhysiol,2007,292(1):H387-391．
[150] Weiss RG,Gerstenblith G,Bottomley PA.ATP flux through creatine kinase in thenormal,stressed,and failing human heart[J].Proc Natl Acad Sci USA,005,02(3):808-813.
[151] Osorio JC, Stanley WC, Linke A, et al. Impaired myocardial fattyacid oxidationand reduced protein expression of retinoid X receptor-alpha in pacing-inducedheart failure[J]. Circulation,2002,106(5):606-612.
[152] Geltman EM, Smith JL, Beecher D, et al. Altered regional myocardialmetabolism in congestive cardiomyopathy detected by positron tomography[J].Am J Med,1983,74(5):773-785.
[153] Dulloo AG,Samec S.Seydoux J.Uncoupling protein3and fatty acidmetabolism[J]. Biochem Soc Trans,2001,29(Pt6):785-791.
[154] Lei B,Lionetti V,Young ME,et al.Paradoxical downregulation of the glucoseoxidation pathway despite enhanced flux in severe heart failure[J].J Mol CellCardiol,2004,36(4):567-576.
[155] Rosenblatt-Velin N, Montessuit C, Papageorgiou I, et al.Postinfarction heartfailure in rats is associated with upregulation of GLUT-1and downregulationof genes of fatty acid metabolism[J]. Cardiovasc Res,2001,52(3):407-416.
[156] Fuentes LD,Herrero P,Peterson LR,et al.Myocardial fatty acid metabolism:ndependent predictor of left ventricular mass in hypertensive heart diseaseJ].Hypertension,2003,41(1):83-87.
[157] Razeghi P,Young ME.Alcorn JL,et al.Metabolic gene expression in fetal andfailing human heart [J].Circulation,2001,104(24):2923-2931.
[158] Moe GW,Matin-Garcia J,Konig A,et a1.In vivo TNF-α inhibition amelioratescardiac mitochondrial dysfunction,oxidative stress,and apoptosis inexperimental heart failure[J].Am J Physiol Heart Circ Physiol,2004,287(4)：H1813-H1820.
[159] Ide T,Tsutsui H,Hayashidani S,et a1.Mitochondrial DNA damage anddysfunction associated with oxidative stress in failing hearts after myocardialinfarction[J].Circ Res,2001,88(5):529-535.
[160] Kuo WW,Chu CY,Wu CH,et al.The profile of cardiac cytochromec oxidaseCOX) xpression in an accelerated cardiac-hypertrophy model[J].J BiomedSci,2005,12(4):601-610.
[161] Kameyama T,Chen Z,Bell SP,et a1.Mechanoenergetic aherations during thetransition from cardiac hypertrophy to failure in Dahl salt-sensitive rats[J].irculation,1998,98(25):2919-2929.
[162] Das AM,Harris DA.Mitochondrial ATP synthase regulation in heart l:defects inhypertension are restored after treatment with captopril[J].Cardioscience,1992,3(4):227-232.
[163] Shertzer HG,Genter MB,Shen D,et a1.TCDD decreases ATP levels andincreases reactive oxygen production through changes in mitochondrialF(0)F(1)-ATP synthase and ubiquinone J].Toxicol Appl Pharmacol,2006,217(3):63-374.
[164] OBrien TX,Schuyler GT,Rackley MS,et a1.F1-ATP synthase beta-subunit andcytochrome c transcriptional regulation in right ventricular hemodynamicoverload and hypertrophically stimulated cardiocytes[J].J Mol CellCardiol,1999,31(1):167-178.
[165] Ning XH,Zhang J,Liu J,et a1.Signaling and expression for mitochondrialmembrane proteins during left ventficular remodelingn and contractile failureafter myocardial infarction[J].J Am Coll Cardiol,2000,36(1):282-287.
[166] Iijima T.Mitochondrial membrane potential and ischemic neuronal death[J].Neurosci Res,2006,55(3):234-243.
[167] Boss O,Hagen T,Lowell BB.Uncoupling proteins2and3: potential regulators ofmitochondrial energymetabolism[J]. Diabetes,2000,49(2):143-156
[168] Sharov VG,Todor A,Khanal S,et a1.Cyclosporine A attenuates mitochondrialpermeability transition and improves mitochondrial respiratory function ineardiomyocytes isolated from dogs with heart failure[J].J Mol CellCardiol,2007,42(1):150-158.
[169] Fukunaga Y,Itoh H,Hosoda K,et a1.Altered gene expression of uncouplingprotein-2and-3in stroke-prone spontaneously hypertensive rats[J].J Hypertens,2000,18(9):1233-1238．
[170] Takimoto E,Kass DA.Role of oxidative stress in cardiac hypertrophy andremodeling[J].Hypertension,2007,49(2):241-248.
[171] CollinA, Cassy S, Buyse J, et al.Potential involvement of mammalian and avianuncoupling proteins in the thermogenic effect of thyroid homones[J].DomestAnim Endocrino,2005,29(1):78-87.
[172] Guan L, GongD, TianN, et al.Uncoupling protein2involved in protection ofglucagons-like peptide2in small intestine with ischemia-reperfusion injury inmice[J].Dig Dis Sci,2005,50(3):554-560.
[173] Nicholls DG. Hamster brown-adipose-tissue mitochondria.purine nucleotidecontrol of the ion conductance of the inner membrane,the nature of thenucleotide binding site[J].Eur J Biochem,1976,62(2):223-228.
[174] Fleury C,Neverova M,Collins S,et al.Uncouling protein-2:a novel gene linked toobesity and hyperinsulinemia[J].Nat Genet,1997,15(3):269-272.
[175] Dalgaard LT,Pedersen O.Uncoupling proteins:functional characteristics and rolein the pathogenesis of obesity and type II diabetes[J].Diabetologia,2001,44(8):946-965.
[176] Jezek P, Urbánková E. Specific sequence of motifs of mitochondrial uncouplingproteins [J]. IUBMB Life,2000,49(1):63-70.
[177][177] eMl oualij B, Duyckaerts C, Lamotte-Brasseur J, et al. Phylogeneticclassification of the mitochondrial carrier family of Saccharomycescerevisiae[J].Yeast,1997,13(6):573-581.
[178] Pecqueur C,Cassard-Doulcier AM,Raimbautt S,et al.Functional organization ofthe human uncoupling protein-2gene,and juxtaposition to the uncouplingprotein-3gene[J].Biochem Biophys Res Commun,1999,255(1):40-46.
[179] Stuart JA,Harper JA,Brindle KM,et al.Physiological levels of mammalianuncoupling protein2do not uncouple yeast mitochondria[J]. J Biol Chem,2001,276(21):18633-18639.
[180] Chavin KD,Yang S,Lin HZ,et al.Obeslty induces expression of uncouplingprotein-2in hepatocytes and promotes liver ATP depletion[J].J Biol Chem,1999,274(9):5692-5700.
[181] Chan CB,De Leo D,Joseph JW,et al. Increased uncoupling protein-2levels inβ-cells associated with impaired glueose-stirnulated insulins secretionmechanism of action[J]. Diabetes,2001,50(6):1302-1310.
[182] Nagase I,Yoshida T,Saito M.Up-regulation of uncoupling proteins bybeta-adrenergic stimulation in L6myotubes[J].FEBS Lett,2001,494(3):175-180.
[183] Zhang CY,Baffy G,Perret P,et al.Uncoupling protein-2negatively regulatesinsulin secretion and is a major link between obesity,beta cell dysfunction,andtype2diabetes[J].Cell2001,105(6):745-755.
[184]顾景范,杜寿玢,查良锭,等.现代临床营养学[M].第1版．北京科学技术出版社,2003,20-33.
[185] St-Pierre J,Buckingham JA,Roebuck SJ,et a1.Topology of Superoxideproduction from Different Sites in the Mitochondrial Electron TransportChain[J].J Biol Chem,2002,277(47):44784-44790.
[186] Karim S,Echtay,Edith Winkler,Karina Frischmuth,et a1.Uncopling Proteins2and3are highly active H(+)transporters and highly nucleotide sensitive whenactivated by coenzyme Q(ubiquinone)[J].Proc Natl Acad Sci USA,2001,98(4):1416-1421.
[187] Pequeur C,Alves-Guerra MC,Gelly C,et a1.Uncoupling protein2, in vivodistribution,induction upon oxidative stress,and evidence for transitionalregulation[J].J Biol Chem,2001,276(12):8705-8712.
[188] Arsenijevic D,Onuma H,Pecquer C,et a1. Disruption of the uncouplingprotein-2gene in mice reveals a role in immunity and reactive oxygen speciesproduction[J].Nat Genet,2000,26(4):435-439.
[189] Jezek P,Hlavatá L.Mitochondria in homeostasis of reactive oxygen species incell,tissues, and organism[J].Int J Biochem Cell Biol,2005,37(12):2478-2503.
[190] Blane J, Alves-Guerra MC, Esposito B, et al. Protective role of uncouplingprotein2in atherosclerosis[J].Circulation,2003,107(3):388-390.
[191] Chan CB, MacDonald PE, Saleh MC, et a1. Overexpression of uncouplingprotein2inhibits glucose-stimulated insulin secretion from rat islets[J].Diabetes,1999,48(7):1482-1486．
[192] Kusmaul L,Hirst J.The mechanism of superoxide production by NADH:ubiquinone oxidoreductase(Complex I) from bovine heart mitochondria[J].ProcNatl Acad Sci USA,2006,103(20):7607-7612．
[193] Echtay KS,Roussel D,St-pierre J,et a1.Superoxide activates mitochondrialuncoupling proteins[J].Nature,2002,415(6867):96-99.
[194] Brand MD,Esteves TC.Physiological functions of the mitochondeial uncouplingprotiens UCP2and UCP3[J].Cell Metab,2005,2(2):85-93.
[195] Wulf Droge.Free radicals in the physiological control of cell function[J].Physiological Rev,2002,82(1):47-95.
[196] Christelle Merial,Anne Bouloumie,Veronique Trocheis,et a1. Nitric oxide-dependent downregulation of adipocyte UCP-2expression by tumor necrosisfactor-α[J].AM J Physiol Cell physiol,2000,279(4):C1100-C1106.
[197] Parish R, Petersen KF.Mitochondrial dysfunction and type2diabetes[J].CurrDiab Rep,2005,5(3):177-183.
[198] Dalgaard LT,Pedersen O.Uncoupling Proteins:functional charaeteristics and rolein the pathogenesis of obesity and type II diabetes[J].Diabetologia,2001,44(8):946-965.
[199] Matarrese P,Gambardella L,Caseone A,et a1.Mitochondrial membranehyperpolarizaation hijacks activated T lymphocytes toward the apoptotic-pronephenotype: homeostatic mechanisms of HIV protease inhibitors[J].J Immunol,2003,170(2):6006-6015.
[200] Kashemsant N,Chan CB.Impact of uncoupling protein-2overexpression onproinsulin processing[J].J Mol Endocrinol,2006,37(3):517-526.
[201] Yasuno K,Ando S,Misumi S,et a1.Synergisfic association of mitochondrialuncoupling protein(UCP)genes with schizophrenia[J].Am J Med Genet BNeuropsychiatr Genet,2007,144B(2):250-253.
[202] Esteves TC,Brand MD.The reactions catalysed by the mitochondrial uncouplingproteins UCP2and UCP3[J].Biochim Biophys Acta,2005,1709(1):35-44.
[203] Hong Y,Fink BD,Dillon JS,et a1.Effects of adenoviral overexpression of UCP-2and-3on mitochondrial respiration in insulinoma cells[J].Endocrinology,2001,142(1):249-256.
[204] Wang X,Axelsson J,Nordfom L,et a1.Changes in fat mass after initiation ofmaintenance dialysis is influenced by the uncoupling protein2exon8insertion/deletion polymorphism[J]. Nephrol Dial Transplant,2007,22(1):196-202.
[205] Park JY,Kim YM,Song HS,et a1.Oleic acid induces endothelin-1expressionthrough activation of protein kinase C and NF-kappa B[J].Biochem Biophys ResCommun,2003,303(3):891-895.
[206] Vogler S, Goedde R, Miterski B, et a1. Association of a common polymorphismin the promoter of UCP2with susceptibility to multiple sclerosis[J].J MolMed,2005,83(10):806-811.
[207] Kashemsant N,Chan CB.Impact of uncoupling protein-2overexpression onproinsulin processing[J].J Mol Endocfinol,2006,37(3):517-526.
[208] Medvedev AV,Snedden SK,Raimbault S,Ricquier D,Collins S.Transcriptionalregulation of the mouse uncoupling protein-2gene.Double E-box motif isrequired for peroxisome proliferator-activated receptor-gamma-dependentactivation[J].J Biol Chem,200l,276(14):10817-10823.
[209] Ogura R,Sugiyama M,Harmaki N,et a1.Electron Spin resonance studies on themechanism of adriamycin-induced heart mitochondrial damages[J].CancerRes,1991,51(13):3555-3558.
[210] Murray AJ, Anderson RE, Watson GC, et a1. Uncoupling proteins in humanheart[J]. Lancet,2004,364(9447):1786-1788.
[211] Murray AJ,Panagia M,Hauton D,et a1. Plasma free acids and peroxisomeproliferators-activated receptor alpha in the control of myocardial uncouplingprotein levels[J].Diabetes,2005,54(12):3496-3502.
[212] Lanni A,Mancini FP,SabatinoL,et a1.De novo expression of uncoupling protein3is associated to enhanced mitochondrial thioesterase-1expression and fattyacid metabo1ism in liver of fenofibrate-treated rats[J].FEBS Lett,2002,525(1-3):7-12.
[213] Reilly JM, Thompson MP. Dietary fatty acids up-regulate the expression ofUCP2in3T3-L1preadipocytes[J]. Biochem Biophys Res Commun,2000,277(3):541-545.
[214] Armstrong MB,Towle HC. Polyunsaturated fatty acids stimulate hepatic UCP-2expression via a PPARalpha-mediated pathway[J]. Am J Physiol EndocrinolMetab,2001,281(6):E1197-1204.
[215] Lentes KU,Tu N,Chen H,et a1.Genomic organization and mutational analysis ofthe human UCP2gene,a prime candidate gene for human obesity[J].J ReceptSignal Transduct Res,1999,19(1-4):229-244.
[216] Acín A, Rodriguez M, Rique H,et a1. Cloning and characterization of the5'flanking region of the human uncoupling protein3(UCP3) gene[J].BiochemBiophys Res Commun,1999,258(2):278-283.
[217] ThompsonMP, Kim D. Links between fatty acids and expression of UCP2andUCP3mRNAs[J]. FEBS Lett,2004,568(1-3):4-9.
[218] Fleury C,Sanchis D.The mitochondrial uncoupling protein-2:current status[J].IntJ Biochem Cell Biol,1999,31(11):1261-1278.
[219] ManciniFP, SabatinoL, ColantuoniVetal. Variants of uncoupling protein-2geneand obesity: interactionwith peroxisome proliferator-activated receptorgamma2[J].Clin Endocrinol (Oxf),2003,59(6):817-822.
[220] Sun x,Zemel MB. Role of uncoupling protein2(UCP2) expression and1alpha,25-dihydroxyvitamin D3in modulating adipocyte apoptosis[J].FASEBJ,2004,18(12):1430-1432.
[221] Hui Zhou, Jing Zhao, Xujia Zhang. Inhibition of uncoupling protein2by genipinreduces insulin-stimulated glucose uptake in3T3-L1adipocytes.Archives ofBiochemistry and Biophysics June.2009;88-93.
[222] Lanni A,De Felice M,Lombardi A,et al. Induction of UCP2mRNA by thyroidhormones in rat heart[J].FEBS Lett,1997,418(1-2):171-174.
[223] Masaki T,Yoshimatsu H,Kakuma T,et al.Enhanced expression of uncouplingprotein2gene in rat white adipose tissue and skeletal muscle following chronictreat ment with thyroid hormone[J]. FEBS Lett,1997,418(3):323-326.
[224] Van Der Lee KA,Willemsen PH,Van Der Vusse GJ,et al.Effects of fatty acids onuncoupling protein-2expression in the rat heart[J]. FASEB J,2000,14(3):495-502.
[225] Voci A,Demori I,Franzi AT,et al.Uncoupling protein2mRNA expression andrespiratory parameters in Kupffer cells isolated from euthyroid and hyperthyroidrat livers[J]. Eur J Endocrinol,2001,145(3):317-322.
[226] Scarpace PJ, Nicolson M, Matheny M, et al. UCP2, UCP3and leptin geneexpression: modulation by food restriction and leptin[J]. J Endocrinol,1998,159(2):349-357.
[227] Ceddia RB,William WN Jr,lima FB,et al.leptin stimulates uncoupling protein-2mRNA expression and Krebs cycle activity and inhibits lipid synthesis inisolated rat white adipocytes [J]. Eur J Biochem,2000,267(19):5952-5958.
[228] KatoH, OhueM, KatoK, et al. Mechanism of amelioration of insulin resistanceby beta3-adrenoceptor agonist AJ-9677in the KK-Ay/Ta diabetic obese mousemodel[J]. Diabetes,2001,50(1):113-122.
[229] Takemoto M, Node K, Nakagami H,et al. Statins as antioxidant therapy forpreventing cardiac myocyte hypertrophy[J]. J Clin Invest,2001,108(10):1429-1437.
[230] Pliquett RU, Cornish KG, Peuler JD,et al. Simvastatin normalizes autonomicneural control in experimental heart failure[J]. Circulation,2003,107(19):2493-2498.
[231]韩磊,叶平,刘永学,等.阿托伐他汀对老年大鼠心肌凋亡和过氧化物体增殖物激活型受体α蛋白表达的影响[J].中国动脉硬化杂志,2009,17(4):256-259.
[232] Faust JR, Brown MS, Goldstein JL. Synthesis of delta2-isopenteny l tRNAfrom mevalonate in cultured human fibroblasts[J].J Biol Chem,1980,255(14):6546-6548.
[233] Tao ZW, Huang YW, Xia Q, Xu QW. Combined effects of ramipril andangiotensin II receptor blocker TCV116on rat congestive heart failure aftermyocardial infarction[J]. Chin Med J (Engl),2005,118(2):146-154.
[234] Wu AH,Feng YJ.Biochemical differences between cTnT and cThI and theirsignificance of diagnosis of acute coronary syndyomes[J].Eur HeartJ,1998,19(Suppl N):N25-N29.
[235] MairJ, Morandell D, Genser N,et al. Euqivalent early sensitivities ofmyoglobin,creatine kinase MB mass,creatine kinase isoform ratios,and cardiactroponins I and T for acute myocardial infarction[J].Clin chem,1995,41(9):1266-1272.
[236] Chauhan D, Pandey P, Ogata A, et al. Cytochrome c-dependent and-independent induction of apoptosis in multiple myeloma cells[J]. J Biol Chem,1997,272(48):29995-29997.
[237] Juranek I, Bezek S. Controversy of free radical hypothesis: reactive oxygenspecies-cause or consequence of tissue injury?[J]. Gen Physiol Biophys,2005,24(3):263-278.
[238] Li JM, Gall NP, Grieve DJ, et al. Activation of NADPH oxidase duringprogression of cardiac hypertrophy to failure[J]. Hypertension,2002,40(4):477-484.
[239] Seshiah PN, Weber DS, Rocic P, et al. Angiotensin II stimulation of NAD(P)Hoxidase activity:upstream mediators[J]. Circ Res,2002,91(5):406-413.
[240] Rikitake Y, Kawashima S, Takeshita S, et al. Anti-oxidative property offluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention ofatherosclerosis in cholesterol-fed rabbits[J]. Atherosclerosis,2001,154(1):87-96.
[241] Wassmann S, Laufs U, Baumer AT, et al. Inhibition of geranylgeranylationreduces angiotensin II-mediated free radical production in vascular smoothmuscle cells: involvement of angiotensin AT1receptor expression and Rac1GTPase[J]. Mol Pharmacol,2001,59(3):646-654.
[242] Molloy CJ,Taylor DS,Weber H.Angiotensin II stimulation of rapid proteintyrosine phosphorylation and protein kinase activation in rat aortic smoothmuscle cells[J].J Biol Chem,1993,268(10):7338-7345.
[243] Eguchi S, Matsumoto T, Motley ED, et al. Identification of an essentialsignaling cascade for mitogen-activated protein kinase activation by angiotensinII in cultured rat vascular smooth muscle cells. Possible requirement ofGq-mediated p21ras activation coupled to a Ca2+/calmodulin-sensitive tyrosinekinase[J].J Biol Chem,1996,271(24):14169-14175.
[244] Sadoshima J, Izumo S. The heterotrimeric G q protein-coupled angiotensin IIreceptor activates p21ras via the tyrosine kinase-Shc-Grb2-Sos pathway incardiac myocytes[J].EMBO J,1996,15(4):775-787.
[245] Davis RJ. The mitogen-activated protein kinase signal transduction pathway[J].JBiol Chem,1993;268(20):14553-14556.