罗格列酮对兔动脉粥样硬化心血管系统超微结构的影响
|
摘要
动脉粥样硬化在发达国家为常见病,在中国,随着生活方式西化,膳食结构的改变和体力运动的减少,本病的发病率逐年增高。吸烟、血脂障碍、高血压、胰岛素抵抗及糖尿病等均为公认的导致动脉粥样硬化的危险因素。动脉粥样硬化的发病原因复杂,很多机制尚不清楚。目前认为它与代谢综合征的关系密切,而胰岛素抵抗是代谢综合征的中心环节,也可能是导致动脉粥样硬化的关键。本研究采用电镜的方法,从形态学的角度出发,探讨了噻唑烷二酮类药物罗格列酮对动脉粥样硬化的作用。将37只健康大耳白兔随机分为空白对照组、动脉粥样硬化组及罗格列酮组,于实验第14周末处死动物,测定血脂、血胰岛素、血糖,电镜观察主动脉及颈动脉结构。研究显示,治疗组血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)低于动脉粥样硬化组,而高密度脂蛋白胆固醇(HDL-C)明显高于后者(P<0.01)。电镜观察发现动脉粥样硬化组存在主动脉及颈动脉内皮下大量脂质沉积,内皮细胞及平滑肌细胞胞浆含较多脂质,胶原纤维增生,内弹力层不均匀变薄,部分缺失,以上均是早期动脉粥样硬化的表现,经罗格列酮治疗后上述情况有明显改善。本研究提示,罗格列酮可能对动脉粥样硬化心血管系统的超微损伤有治疗作用。
Artherosclerosis is common in developed nations and have reached epidemic proportions in many developing nations . Potential causes of this growing epidemic in China include changes in dietary patterns,physical inactivity,obesity,aging stage and environmental determinants. The major cause of myocardial infarction(MI)and cerebral ischemia is artherosclerosis which acutely has threaten the health of people.So it is important to develop the new therapy and drug.
Metabolic syndrome (MS),a cluster of risk factors, such as obesity,hypertension,dyslipidemia,hyperglycemia,hyperuricacidemia and so on, contributes to the development of cardio-vascular diseases and type 2 diabetes mellitus (DM2). Moreover those risk factors effect each other, which contribute to the development of cardiovascular and cerebrovascular diseases together. Insulin resistance (IR) plays a key role in MS, we can delay the proceeding of those diseases through improving IR effectually.
Rosiglitazone, an insulin sensitizer, is well recognized that amelioration of hyperinsulinaemia and hyperglycaemia, can delay the onset of vascular complications through improving IR. Rosiglitazone can affect peroxisome proliferator-activated receptor (PPAR)-gamma which belongs to the nuclear hormone receptor superfamily. (PPAR)-gamma plays a part in the cytodifferentiation of adipose cell, glycometabolism, lipid metabolism and inflammatory reaction.So we expect beneficial effects of rosiglitazone for the treatment and prevention of atherosclerosis.
The purpose of this study was to determine the effects of rosiglitazone on dyslipidemia and atherosclerotic ultramicrostructure. Our study results show that rosiglitazone is available as a new type of antiatherogenic and also provide us new clues to find more effective drug.
Methods:
We selected 37 male Japanese albino rabbits, age 7-8 weeks. All rabbits were randomly divided into three groups: (1) Control group: fed with ordinary fodder 2 times a day; (2) AS group: fed with high fat fodder (120-150g/d) and ordinary fodder; (3) rosiglitazone group: fed with fodder mixed uniformly with rosiglitazone (1.5mg/kg) every morning, then high fat fodder and ordinary fodder. At the beginning of the experiment, we injected the habbits of the last two groups with bovine serum albumin (1g/kg), and the blank group with tales doses of normal saline.We plan the whole experiment time is 14 weeks. At the end of the experiment, we anesthetized rabbits with 10% chloral hydrate, splited the cavitas thoracis and abdominal cavity along the anterior median line, and collected the whole blood from heart. We detected immediately TC,TG, HDL-C, LDL-C, FBG, evaluated blood insulin with radio immunoassay and calculated HOMA-IR. We put out their arteriae aorta and arteria cervicalis which were made into samples. We measured the areas of plaque and total endangium, and calculated the proportion of plaque area to the total endangium area. At the end of the experiment, we applied electron microscope to observe histopathological changes of arteriae aorta and arteria cervicalis.
Results:
Retroperitoneal adipose tissue of AS group was more than those of rosiglitazone group.The blood serum of control group appeared transparent, on the contrary, the appearance of the other two groups were ivory white and turbid.The levels of TC, TG, LDL-C and HDL-C of the rosiglitazone group and AS group were higher than those of control group. Compared with AS group, the level of HDL-C of rosiglitazone group was 39.69% higher but levels of TC, TG, LDL-C was lower.
There was not visible atherosclerotic plaque in the arteriae aorta of blank group, through magdala red stain examination. In the arteriae aorta endangium of AS group, we found a large areas of atheromatous plaque extensively, and the proportion of plaque area was 74.68±11.89%. The consequence was different referred to endangium of rosiglitazone group,there was only discontinuous and slight scleratheroma plaque. The proportion of plaque area in rosiglitazone group was 29.93±11.54%, which was lower than that of AS group by 59.92%.
The histopathological changes(electron microscope examination), arteriae aorta and arteria cervicalis of AS group shows: (1) There is a great quantity Lipidoses in intracytoplasm of endotheliocyte and contractile fiber cells. (2) The elastic layer is tenuis and uneven, even missing in some parts. (3) We see that the space is enlarged between endotheliocyte and elastic layer. (4) There is some collagen fibers accrementition with irregular arrangement.
The arteriae aorta and arteria cervicalis of rosiglitazone group show the features: (1)endothelial cell are integrity , there is a small quantity Lipidoses in it. (2) The elastic layer is Integrity uniformity. (3) compared with the arteriae aorta endangium of AS group, there is a little collagen fibers accrementition.
Conclusion:
Compared with AS group, rabbits of rosiglitazone group were in good condition. Retroperitoneal adipose tissue of AS group was accumulated, but those rabbits' adipose tissue decreased because of taking rosiglitazone consecutively. The sign of Lipidoses in Intracytoplasm of endotheliocyte,collagen fibers accrementition and tenuis elastic layer showed earlier period of artherosclerosis. Those histopathological changes could lead to angiostegnosis, atherosclerotic plaque,disruption and vascular occlusion.
After the therapy of taking rosiglitazone, those abnormal appearance of endangium was remarkably improved. Furthermore, The level of HDL-C of rosiglitazone group was higher but levels of TC, TG, LDL-C was lower. The results shows that the protective effects of rosiglitazone on the ultramicrostructure of cardiovascular system of atherosclerosis of rabbits is certain.
Artherosclerosis is common in developed nations and have reached epidemic proportions in many developing nations . Potential causes of this growing epidemic in China include changes in dietary patterns,physical inactivity,obesity,aging stage and environmental determinants. The major cause of myocardial infarction(MI)and cerebral ischemia is artherosclerosis which acutely has threaten the health of people.So it is important to develop the new therapy and drug.
Metabolic syndrome (MS),a cluster of risk factors, such as obesity,hypertension,dyslipidemia,hyperglycemia,hyperuricacidemia and so on, contributes to the development of cardio-vascular diseases and type 2 diabetes mellitus (DM2). Moreover those risk factors effect each other, which contribute to the development of cardiovascular and cerebrovascular diseases together. Insulin resistance (IR) plays a key role in MS, we can delay the proceeding of those diseases through improving IR effectually.
Rosiglitazone, an insulin sensitizer, is well recognized that amelioration of hyperinsulinaemia and hyperglycaemia, can delay the onset of vascular complications through improving IR. Rosiglitazone can affect peroxisome proliferator-activated receptor (PPAR)-gamma which belongs to the nuclear hormone receptor superfamily. (PPAR)-gamma plays a part in the cytodifferentiation of adipose cell, glycometabolism, lipid metabolism and inflammatory reaction.So we expect beneficial effects of rosiglitazone for the treatment and prevention of atherosclerosis.
The purpose of this study was to determine the effects of rosiglitazone on dyslipidemia and atherosclerotic ultramicrostructure. Our study results show that rosiglitazone is available as a new type of antiatherogenic and also provide us new clues to find more effective drug.
Methods:
We selected 37 male Japanese albino rabbits, age 7-8 weeks. All rabbits were randomly divided into three groups: (1) Control group: fed with ordinary fodder 2 times a day; (2) AS group: fed with high fat fodder (120-150g/d) and ordinary fodder; (3) rosiglitazone group: fed with fodder mixed uniformly with rosiglitazone (1.5mg/kg) every morning, then high fat fodder and ordinary fodder. At the beginning of the experiment, we injected the habbits of the last two groups with bovine serum albumin (1g/kg), and the blank group with tales doses of normal saline.We plan the whole experiment time is 14 weeks. At the end of the experiment, we anesthetized rabbits with 10% chloral hydrate, splited the cavitas thoracis and abdominal cavity along the anterior median line, and collected the whole blood from heart. We detected immediately TC,TG, HDL-C, LDL-C, FBG, evaluated blood insulin with radio immunoassay and calculated HOMA-IR. We put out their arteriae aorta and arteria cervicalis which were made into samples. We measured the areas of plaque and total endangium, and calculated the proportion of plaque area to the total endangium area. At the end of the experiment, we applied electron microscope to observe histopathological changes of arteriae aorta and arteria cervicalis.
Results:
Retroperitoneal adipose tissue of AS group was more than those of rosiglitazone group.The blood serum of control group appeared transparent, on the contrary, the appearance of the other two groups were ivory white and turbid.The levels of TC, TG, LDL-C and HDL-C of the rosiglitazone group and AS group were higher than those of control group. Compared with AS group, the level of HDL-C of rosiglitazone group was 39.69% higher but levels of TC, TG, LDL-C was lower.
There was not visible atherosclerotic plaque in the arteriae aorta of blank group, through magdala red stain examination. In the arteriae aorta endangium of AS group, we found a large areas of atheromatous plaque extensively, and the proportion of plaque area was 74.68±11.89%. The consequence was different referred to endangium of rosiglitazone group,there was only discontinuous and slight scleratheroma plaque. The proportion of plaque area in rosiglitazone group was 29.93±11.54%, which was lower than that of AS group by 59.92%.
The histopathological changes(electron microscope examination), arteriae aorta and arteria cervicalis of AS group shows: (1) There is a great quantity Lipidoses in intracytoplasm of endotheliocyte and contractile fiber cells. (2) The elastic layer is tenuis and uneven, even missing in some parts. (3) We see that the space is enlarged between endotheliocyte and elastic layer. (4) There is some collagen fibers accrementition with irregular arrangement.
The arteriae aorta and arteria cervicalis of rosiglitazone group show the features: (1)endothelial cell are integrity , there is a small quantity Lipidoses in it. (2) The elastic layer is Integrity uniformity. (3) compared with the arteriae aorta endangium of AS group, there is a little collagen fibers accrementition.
Conclusion:
Compared with AS group, rabbits of rosiglitazone group were in good condition. Retroperitoneal adipose tissue of AS group was accumulated, but those rabbits' adipose tissue decreased because of taking rosiglitazone consecutively. The sign of Lipidoses in Intracytoplasm of endotheliocyte,collagen fibers accrementition and tenuis elastic layer showed earlier period of artherosclerosis. Those histopathological changes could lead to angiostegnosis, atherosclerotic plaque,disruption and vascular occlusion.
After the therapy of taking rosiglitazone, those abnormal appearance of endangium was remarkably improved. Furthermore, The level of HDL-C of rosiglitazone group was higher but levels of TC, TG, LDL-C was lower. The results shows that the protective effects of rosiglitazone on the ultramicrostructure of cardiovascular system of atherosclerosis of rabbits is certain.
引文
1. 程歆琦. 代谢综合征与血脂异常[J]. 国外医学临床生物化学与检验学分册,2005;26(2):77-79.
2. Lele RD. Causation, prevention and reversal of vascular endothelial dysfunction[J]. J Assoc Physicians India, 2007;55: 643-51.
3. Brame L, Verma S, Anderson T, et al. Insulin resistance as a therapeutic target for improved endothelial function:metformin [J]. Curr Drug Targets Cardiovasc HaematolD isord, 2004;4 (1):53-63.
4. Mouco OM, Nicolau JC, Souza Tda R,et al. Inflammatory markers of atherosclerotic plaque stabilization after acute coronary event-temporal trends[J]. Arq Bras Cardiol, 2006;87(1):28-36.
5. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease[J]. Diabetes, 1988;37(12):1595-607.
6. 王辉,姜燕, 张凤岭,等. 胰岛素抵抗与动脉粥样硬化的相关性研究[J]. 济宁医学院学报. 2005;28(3):30-32.
7. LAIGHTDW, CARRIER L. Antioxidants, diabetes and endothelial dysfunction[J]. Cardiovascular Research, 2000;47(3): 457-64.
8. 方莲花, 杜冠华. 晚期糖基化终产物和抗动脉粥样硬化药物发现策略[J]. 中国药学杂志, 2007;42(11): 801-4.
9. Han SH, Quon MJ, Koh KK. Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction [J].Curr Opin Lipidol. 2007;18(1):58-65.
10. 郭晓珍. 噻唑烷二酮类药物抗动脉粥样硬化的作用机制[J]. 国外医学内科学分册, 2005;32(4):172-176.
11. 黄斌, 罗琳, 韩文群,等. 马来酸罗格列酮对 2 型糖尿病患者糖脂代谢、胰岛素抵抗及血清炎症因子的影响[J]. 中国糖尿病杂志, 2006;14 (1):9-10.
12. 赵全明, 颜东, 宋爱丽, 等. 罗格列酮对 ApoE 基因敲除小鼠动 脉 粥 样 硬 化 的 影 响 [J]. 中 华 心 血 管 病 杂 志 , 2005; 33(5):399-404.
13. Todd MK, Watt MJ, Le J. Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance [J]. Am J Physiol Endocrinol Metab, 2007;292(2):485-93.
14. Koh EH, Lee WJ, Kim MS. Intracellular Fatty Acid metabolism in skeletal muscle and insulin resistance[J].Curr Diabetes Rew, 2005;1(3):331-6.
15. 凌宏艳, 奉水东, 胡必利. 罗格列酮对胰岛素抵抗大鼠内皮细 胞 内 分 泌 功 能 的 影 响 [J]. 中 华 内 分 泌 代 谢 杂 志 , 2006;22(1):26-27.
16. Law RE, Goetze S, Xi XP, et al. Expression and function ofPPARgamma in rat and human vascular smooth muscle cells[J]. Circulation, 2000;101(11):1311-8.
17. Gaikwad AB, Viswanad B, Ramarao P. PPAR gamma agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance[J]. Pharmacol Res, 2007;55(5):400-7.
18. Young PW, Buckle DR, Cantello BC.Identification of high-affinity bindingsites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and humanadipocytes using a radioiodinated ligand for peroxisomal proliferator-activated recepror gamma[J]. J Pharmacol Exp Ther, 1998;284:751-759.
19. Todd MK, Watt MJ, Le J,et al.Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance[J]. Am J Physiol Endocrinol Metab, 2007;292(2):485-93.
20. Askari B, Kanter JE, Sherrid AM, et al. Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator- activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages[J]. Diabetes, 2007;56(4):1143-52.
21. Mazzone T, Meyer PM, Feinstein SB,et al .Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial[J]. JAMA, 2006 6;296(21): 2572-81.
22. 中华医学会糖尿病学分会代谢综合征研究所协作组. 中华医学会糖尿病学分会关于代谢综合征的建议[J]. 中华糖尿病杂志, 2004;12:156-161.
23. Abbasi F, McLaughlin T, Lamendola C, et al. Insulin regulation of plasma free fatty acid concent rations is abnormal in healthy subjects with muscle insulin resistance[J]. Metabolism, 2000;49 (2):151-154.
24. Dullaart RP, van-Tol A. Role of phospholipid transferprotein and prebeta-high density lipoproteins in maintainingcholesterol efflux from Fu5AH cells to plasma from insulin-resistant subjects[J]. Scand J Clin Lab Invest, 2001;61(1):69-74.
25. Steinberg HO,B rechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release[J]. J Clin Invest, 1994;94 (3):1172-1179.
26. Ross R. Mechanisms of atherosclerosis-a review[J]. Adv Nephrol Necker Hosp, 1990;19:79-86.
27. Ross R. Atheroclesis-An inflammatory disease[J]. N Engl J Med, 1999,340(2):115-126.
28. Pradhan A. Obesity, metabolic syndrome and type 2 diabetes: inflammatory basis of glucose metabolic disorders[J]. Nutr Rev,2007;65(12 Pt 2):152-6.
29. Be?towski J, Jamroz-Wi?niewska A, Widomska S. Adiponectin and its role in cardiovascular diseases[J]. Cardiovasc Hematol Disord Drug Targets, 2008;8(1):7-46.
30. Zhu W, Cheng KK, Vanhoutte PM, et al. Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention[J]. Clin Sci(Lond), 2008;114(5):361-74.
31. Tabara Y, Osawa H, Kawamoto R. Reduced high-molecular weight adiponectin and elevated hsCRP are synergistic risk factors for metabolic syndrome in a large scale middle-aged to elderly population:the J-SHIPP study[J]. J Clin Endocrinol Metab, 2007;130(5):430-41.
32. Dollery CM.Matrix metalloproteinases and cardiovascular disease [J]. CircRes, 1995;77:863-8.
33. Fitzsimmons PJ, Forough R, Lawrence ME, et al. Urinary levels of matrix metalloproteinase 9 and 2 and tissue inhibitor of matrix metalloproteinase in patients with coronary artery disease[J]. Atherosclerosis, 2007;194(1):196-203.
34. Zeng B, Prasan A, Fung KC. Elevated circulating levels of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease[J]. Intern Med J, 2005;35(6):331-5.
35. 康闽, 韦卫中, 王宏伟. 免疫性血管炎致动脉粥样硬化的实验研究[J]. 实用儿科临床杂志, 2003;18(3):166-8.
36. Fukunaga Y, Itoh H, Doi K, et al. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides[J]. Atherosclerosis, 2001;158(1):113-9.
37. Salomonsson L, Svensson L, Pettersson S,et al. Oxidised LDL decreases VEGFR-1 expression in human monocyte-derived macrophages[J]. Atherosclerosis, 2003;169(2):259-67.
38. Sheu WH, Ou HC, Chou FP.Rosiglitazone inhibits endothelial proliferation and angiogenesis[J]. Life Sci, 2006;78(13):1520-8.
39. 刘宽芝, 吕海莉, 王伟超. 罗格列酮对2型糖尿病大鼠大血管病变的防治作用及其分子机制[J]. 中国动脉硬化杂志, 2006;14(2):93-96.
40. 吕海莉, 韩恒利, 吴建民等. 罗格列酮对2型糖尿病合并颈动脉粥样硬化患者血清基质金属蛋白酶-9及C-反应蛋白的影响[J]. 临床内科杂志, 2006;23(50):334-6.
41. Rodríguez-Lee M, Ostergren-Lundén G, Wallin B.Fatty acids cause alterations of human arterial smooth muscle cell proteoglycans that increase the affinity for low-density lipoprotein[J]. Arterioscler Thromb Vasc Biol,2006;26(1):130-5.
42. Johnson JA, Trasino SE, Ferrante AW Jr.Prolonged decrease of adipocyte size after rosiglitazone treatment in high-and low-fat- fed rats[J]. Obesity(Silver Spring), 2007;15(11):2653-63
43. 王萍萍, 邵明柏, 王新莉. 罗格列酮对兔血脂紊乱及动脉脂质沉积的影响[J]. 中国老年学杂志, 2007;27(6):537-9.
44. Li AC, Brown KK, Silvestre MJ. Peroxisome proliferator -activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor-deficient mice[J].J Clin Invest, 2000;106:523-31.
45. Schwartz AV, Sellmeyer DE. Effect of thiazolidinediones on skeletal health in women with Type 2 diabetes[J]. Expert Opin Drug Saf, 2008;7(1):69-78.
46. Grey A. Skeletal consequences of thiazolidinedione therapy[J]. Osteoporos Int, 2008;19(2):129-37.
47. Murphy CE, Rodgers PT. Effects of thiazolidinediones on bone loss and fracture[J]. Ann Pharmacother, 2007;41(12):2014-8.
2. Lele RD. Causation, prevention and reversal of vascular endothelial dysfunction[J]. J Assoc Physicians India, 2007;55: 643-51.
3. Brame L, Verma S, Anderson T, et al. Insulin resistance as a therapeutic target for improved endothelial function:metformin [J]. Curr Drug Targets Cardiovasc HaematolD isord, 2004;4 (1):53-63.
4. Mouco OM, Nicolau JC, Souza Tda R,et al. Inflammatory markers of atherosclerotic plaque stabilization after acute coronary event-temporal trends[J]. Arq Bras Cardiol, 2006;87(1):28-36.
5. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease[J]. Diabetes, 1988;37(12):1595-607.
6. 王辉,姜燕, 张凤岭,等. 胰岛素抵抗与动脉粥样硬化的相关性研究[J]. 济宁医学院学报. 2005;28(3):30-32.
7. LAIGHTDW, CARRIER L. Antioxidants, diabetes and endothelial dysfunction[J]. Cardiovascular Research, 2000;47(3): 457-64.
8. 方莲花, 杜冠华. 晚期糖基化终产物和抗动脉粥样硬化药物发现策略[J]. 中国药学杂志, 2007;42(11): 801-4.
9. Han SH, Quon MJ, Koh KK. Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction [J].Curr Opin Lipidol. 2007;18(1):58-65.
10. 郭晓珍. 噻唑烷二酮类药物抗动脉粥样硬化的作用机制[J]. 国外医学内科学分册, 2005;32(4):172-176.
11. 黄斌, 罗琳, 韩文群,等. 马来酸罗格列酮对 2 型糖尿病患者糖脂代谢、胰岛素抵抗及血清炎症因子的影响[J]. 中国糖尿病杂志, 2006;14 (1):9-10.
12. 赵全明, 颜东, 宋爱丽, 等. 罗格列酮对 ApoE 基因敲除小鼠动 脉 粥 样 硬 化 的 影 响 [J]. 中 华 心 血 管 病 杂 志 , 2005; 33(5):399-404.
13. Todd MK, Watt MJ, Le J. Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance [J]. Am J Physiol Endocrinol Metab, 2007;292(2):485-93.
14. Koh EH, Lee WJ, Kim MS. Intracellular Fatty Acid metabolism in skeletal muscle and insulin resistance[J].Curr Diabetes Rew, 2005;1(3):331-6.
15. 凌宏艳, 奉水东, 胡必利. 罗格列酮对胰岛素抵抗大鼠内皮细 胞 内 分 泌 功 能 的 影 响 [J]. 中 华 内 分 泌 代 谢 杂 志 , 2006;22(1):26-27.
16. Law RE, Goetze S, Xi XP, et al. Expression and function ofPPARgamma in rat and human vascular smooth muscle cells[J]. Circulation, 2000;101(11):1311-8.
17. Gaikwad AB, Viswanad B, Ramarao P. PPAR gamma agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance[J]. Pharmacol Res, 2007;55(5):400-7.
18. Young PW, Buckle DR, Cantello BC.Identification of high-affinity bindingsites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and humanadipocytes using a radioiodinated ligand for peroxisomal proliferator-activated recepror gamma[J]. J Pharmacol Exp Ther, 1998;284:751-759.
19. Todd MK, Watt MJ, Le J,et al.Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance[J]. Am J Physiol Endocrinol Metab, 2007;292(2):485-93.
20. Askari B, Kanter JE, Sherrid AM, et al. Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator- activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages[J]. Diabetes, 2007;56(4):1143-52.
21. Mazzone T, Meyer PM, Feinstein SB,et al .Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial[J]. JAMA, 2006 6;296(21): 2572-81.
22. 中华医学会糖尿病学分会代谢综合征研究所协作组. 中华医学会糖尿病学分会关于代谢综合征的建议[J]. 中华糖尿病杂志, 2004;12:156-161.
23. Abbasi F, McLaughlin T, Lamendola C, et al. Insulin regulation of plasma free fatty acid concent rations is abnormal in healthy subjects with muscle insulin resistance[J]. Metabolism, 2000;49 (2):151-154.
24. Dullaart RP, van-Tol A. Role of phospholipid transferprotein and prebeta-high density lipoproteins in maintainingcholesterol efflux from Fu5AH cells to plasma from insulin-resistant subjects[J]. Scand J Clin Lab Invest, 2001;61(1):69-74.
25. Steinberg HO,B rechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release[J]. J Clin Invest, 1994;94 (3):1172-1179.
26. Ross R. Mechanisms of atherosclerosis-a review[J]. Adv Nephrol Necker Hosp, 1990;19:79-86.
27. Ross R. Atheroclesis-An inflammatory disease[J]. N Engl J Med, 1999,340(2):115-126.
28. Pradhan A. Obesity, metabolic syndrome and type 2 diabetes: inflammatory basis of glucose metabolic disorders[J]. Nutr Rev,2007;65(12 Pt 2):152-6.
29. Be?towski J, Jamroz-Wi?niewska A, Widomska S. Adiponectin and its role in cardiovascular diseases[J]. Cardiovasc Hematol Disord Drug Targets, 2008;8(1):7-46.
30. Zhu W, Cheng KK, Vanhoutte PM, et al. Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention[J]. Clin Sci(Lond), 2008;114(5):361-74.
31. Tabara Y, Osawa H, Kawamoto R. Reduced high-molecular weight adiponectin and elevated hsCRP are synergistic risk factors for metabolic syndrome in a large scale middle-aged to elderly population:the J-SHIPP study[J]. J Clin Endocrinol Metab, 2007;130(5):430-41.
32. Dollery CM.Matrix metalloproteinases and cardiovascular disease [J]. CircRes, 1995;77:863-8.
33. Fitzsimmons PJ, Forough R, Lawrence ME, et al. Urinary levels of matrix metalloproteinase 9 and 2 and tissue inhibitor of matrix metalloproteinase in patients with coronary artery disease[J]. Atherosclerosis, 2007;194(1):196-203.
34. Zeng B, Prasan A, Fung KC. Elevated circulating levels of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease[J]. Intern Med J, 2005;35(6):331-5.
35. 康闽, 韦卫中, 王宏伟. 免疫性血管炎致动脉粥样硬化的实验研究[J]. 实用儿科临床杂志, 2003;18(3):166-8.
36. Fukunaga Y, Itoh H, Doi K, et al. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides[J]. Atherosclerosis, 2001;158(1):113-9.
37. Salomonsson L, Svensson L, Pettersson S,et al. Oxidised LDL decreases VEGFR-1 expression in human monocyte-derived macrophages[J]. Atherosclerosis, 2003;169(2):259-67.
38. Sheu WH, Ou HC, Chou FP.Rosiglitazone inhibits endothelial proliferation and angiogenesis[J]. Life Sci, 2006;78(13):1520-8.
39. 刘宽芝, 吕海莉, 王伟超. 罗格列酮对2型糖尿病大鼠大血管病变的防治作用及其分子机制[J]. 中国动脉硬化杂志, 2006;14(2):93-96.
40. 吕海莉, 韩恒利, 吴建民等. 罗格列酮对2型糖尿病合并颈动脉粥样硬化患者血清基质金属蛋白酶-9及C-反应蛋白的影响[J]. 临床内科杂志, 2006;23(50):334-6.
41. Rodríguez-Lee M, Ostergren-Lundén G, Wallin B.Fatty acids cause alterations of human arterial smooth muscle cell proteoglycans that increase the affinity for low-density lipoprotein[J]. Arterioscler Thromb Vasc Biol,2006;26(1):130-5.
42. Johnson JA, Trasino SE, Ferrante AW Jr.Prolonged decrease of adipocyte size after rosiglitazone treatment in high-and low-fat- fed rats[J]. Obesity(Silver Spring), 2007;15(11):2653-63
43. 王萍萍, 邵明柏, 王新莉. 罗格列酮对兔血脂紊乱及动脉脂质沉积的影响[J]. 中国老年学杂志, 2007;27(6):537-9.
44. Li AC, Brown KK, Silvestre MJ. Peroxisome proliferator -activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor-deficient mice[J].J Clin Invest, 2000;106:523-31.
45. Schwartz AV, Sellmeyer DE. Effect of thiazolidinediones on skeletal health in women with Type 2 diabetes[J]. Expert Opin Drug Saf, 2008;7(1):69-78.
46. Grey A. Skeletal consequences of thiazolidinedione therapy[J]. Osteoporos Int, 2008;19(2):129-37.
47. Murphy CE, Rodgers PT. Effects of thiazolidinediones on bone loss and fracture[J]. Ann Pharmacother, 2007;41(12):2014-8.