电针“内关”对心肌肥厚大鼠P38MAPK信号通路的影响
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摘要
目的
心肌肥厚是许多心血管疾病发展的一个重要阶段,在先天性心脏病、心肌梗死、心脏瓣膜病、高血压等多种心血管疾病中,心肌肥厚是共有的病理过程,持续的外界刺激引起心肌肥厚不断进展,使心肌氧耗量增加及顺应性降低,最终导致心脏扩大、充血性心力衰竭甚至猝死,是心血管疾病患病率和死亡率增加的独立危险因素,随着左室肥厚的发生、发展,猝死、室性心律失常、心肌缺血、心力衰竭等心血管事件的发生率增加6-10倍。药物等治疗取得了较好的疗效,但所带来的副作用和临床效应还需进一步验证,介入疗法虽然能改善患者的生活质量,然而作为有创性的治疗技术不可避免地会发生各种并发症,如血管迷走神经反射、血管内血栓形成、胸闷、胸痛,甚至导致死亡。因此,如何探明心肌肥厚发生机制,积极有效的防治心肌肥厚,减少心血管疾病病死率和发病率已成为国内外心血管领域研究热点和焦点。针灸作为低损伤的治疗方法在心脏病的防治中具有较好的疗效并且已广泛应用于临床。本课题在“心胸内关谋”经验总结和前期研究基础上,运用现代医学理论与实验方法研究电针“内关”对心肌肥厚大鼠心肌组织P38MAPK信号通路的影响及作用机制,对临床防治各种病因的心肌肥厚具有十分重要的理论意义和实用价值。
方法
3月龄雌性SD大鼠50只,体重180g左右,查随机数字表分为5组：正常组、模型组、电针组、p38抑制剂组、电针+p38抑制剂组,每组10只。正常组：每日颈背部皮下注射生理盐水3mg/kg·d；模型组：以IS03mg/kg·d颈背部皮下注射14d制备心肌肥厚模型,连续14天；以心电图的改变：QRS波和QT波持续时间延长(QRS>0.10s),T波形态改变作为造模成功的标志；电针组：每日颈背部皮下注射IS03.0mg/kg,针刺双侧“内关”深度约5mm,接HANS-200电针治疗仪,选用连续波,频率2Hz,强度为1mA,通电20min,1次／d,14d；p38抑制剂组：每日颈背部皮下注射IS03.0mg/kg, p38丝裂原激活蛋白激酶特异性抑制剂SB203580,以0.3mg/kg/d颈背部皮下注射,连续14d；电针+p38抑制剂组：每日颈背部皮下注射IS03.0mg/kg,SB203580以0.3mg/kg/d颈背部皮下注射,双侧“内关”穴接HANS-200电针治疗仪,选用连续波,频率2Hz,强度为1mA,通电20min,1次／d,14d。大鼠于第15天称取体重、左心室重量和全心重量,并计算左心室重量指数和全心重量指数,心肌组织HE染色,测量左心室壁平均厚度、心肌细胞平均直径、心肌纤维横径,硝酸还原酶法测定血清和心肌组织NO含量,放射免疫法检测血清和心肌组织TNF-α、IL-1β含量,免疫组织化学法检测心肌p38MAPK.p-p38MAPK免疫阳性细胞表达；蛋白质免疫印迹法检测p38MAPK.p-p38MAPK活性,运用图象分析系统进行检测,并对数据进行统计分析。
结果
1.模型组大鼠HW、LVW、HWI、LVWI于造模后升高,均明显高于正常组,有非常显著性差异义(p<0.01)；电针组、p38抑制剂组、电针+p38抑制剂组大鼠HW、LVW、HWI、LVWI均明显低于模型组,有显著性差异(p<0.05)；电针组、p38抑制剂组、电针+p38抑制剂组之间无显著性差异(p>0.05)。
2.模型组大鼠左心室壁平均厚度、心肌细胞平均直径、心肌纤维横径于造模后升高,和正常组比较,有非常显著性差异(p<0.01)；电针组、p38抑制剂组、电针+p38抑制剂组大鼠左心室壁平均厚度、心肌细胞平均直径、心肌纤维横径均明显低于模型组,和模型组比较有显著性差异(p<0.05),电针+p38抑制剂组和模型组比较,有非常显著性差异(p<0.01),三组之间比较无显著性差异(p>0.05)。
3.正常组心肌细胞染色后心肌结构清晰、完整、均匀,心肌纤维排列整齐,横纹清楚,无形态异常；模型组心肌细胞染色不均,心肌纤维走向紊乱,心肌纤维横径增加,心肌纤维之间的结缔组织疏松水肿、增生,细胞大小不均,心肌细胞直径明显变大,电针组、p38抑制剂组、电针+p38抑制剂组治疗后,心肌细胞稍大,排列尚可,心肌细胞肥厚程度较模型组减轻,心肌纤维排列稍整齐,水肿和增生明显改善。
4.模型组大鼠心肌组织和血清N0含量于造模后降低,均明显低于正常组,有非常显著性差异义(p<0.01)；电针组、p38抑制剂组、电针+p38抑制剂组大鼠NO均明显高于模型组,有显著性差异(p<0.05)；三组之间无显著性差异(p>0.05)
5.模型组大鼠心肌组织和血清TNF-α、IL-1β含量于造模后升高,和正常组比较,有非常显著性差异(p<0.01)；电针组、p38抑制剂组、电针+p38抑制剂组大鼠TNF-α、IL-1β含量均明显低于模型组,和模型组比较,有显著性差异(p<0.05),三组之间比较无显著性差异(p>0.05)。
6.造模后p38MAPK、p-p38MAPK免疫阳性物增多,平均积分光密度值明显高于正常组,和正常组比较,有非常显著性差异(p<0.01)；电针组、p38抑制剂组大鼠平均积分光密度值均明显低于模型组,和模型组比较,有显著性差异(p<0.05),电针+p38抑制剂组有非常显著性差异(p<0.01),三组之间比较无显著性差异(p>0.05)。
7.模型组大鼠心肌细胞p38MAPK、p-p38MAPK于造模后升高,和正常组比较,有非常显著性差异(p<0.01)；电针组、p38抑制剂组p38MAPK、 p-p38MAPK均明显低于模型组,有显著性差异(p<0.05),电针+p38抑制剂组和模型组比较有非常显著性差异(p<0.01),三组之间比较无显著性差异(p>0.05)
结论
1.电针“内关”穴可使心肌肥厚模型大鼠全心重量指数、左室重量指数下降,左心室壁平均厚度下降；心肌细胞平均直径和心肌纤维横径减小,对心肌形态学有明显改善。
2.电针“内关”穴可使心肌肥厚模型大鼠血清和心肌组织NO含量升高,其抗心肌肥厚作用可能是通过升高NO来实现的。
3.电针“内关”穴可以防治心肌肥厚,这种保护作用可能与抑制TNF-a、IL-1β等炎性因子的表达实现对p38MAPK信号通路调节有关。
4. P38MAPK信号转导通路参与异丙肾上腺致大鼠心肌肥厚过程,P38MAPK表达上调促进心肌肥厚发生,电针“内关”穴可以明显抑制心肌肥厚p38MAPK的磷酸化,对心肌细胞p38信号转导通路的调节可能是电针“内关”防治心肌肥厚的作用机制之一
5.电针、p38抑制剂、电针+p38抑制剂防治心肌肥厚结果比较并未见明显差异,电针+p38抑制剂并未出现叠加效应,可能与p38抑制剂对信号通路的抑制作用较强,掩盖了部分电针“内关”效应有关。
Objective
Cardiac hypertrophy is an important stage in the development of cardiovascular disease. In congenital heart disease, myocardial infarction,valvular heart disease, hypertension and other cardiovascular diseases,cardiac hypertrophy is a common pathological process. The continuous stimulation from outside causes the continuous progress of cardiac hypertrophy, it also increases the myocardial oxygen consumption and reduces compliance, eventually leads to cardiac enlargement, congestive heart failure and even sudden death,so it is an independent risk factor for the increasing cardiovascular disease morbidity and mortality. With the occurrence and development of left ventricular hypertrophy, sudden death, ventricular arrhythmia, myocardial ischemia, heart failure and other cardiovascular events rate increases by6-10times. Drug treatments achieve a good effect, but the side effects and clinical effects need further verification. Intervention therapy can improve the quality of life of patients, however,as an invasive treatment technology it will inevitably have a variety of complications, such as vasovagal reflex, vascular thrombosis,chest tightness, chest pain,or even leading to death. Therefore, finding out the function mechanism of cardiac hypertrophy, treating and preventing myocardial hypertrophy positive and effective, reducing cardiovascular disease mortality and morbidity rates have become the hot spots and focuses in the field of cardiovascular research all over the world. Acupuncture, as a low-injury treatment with good effect in the prevention and treatment of heart disease, has been widely used in cl inical. Guiding by the theory of Chinese acupuncture "for heart and chest, it is point Neiguan" and on the basis of preliminary studies,with modern medical theory and experimental methods,this experiment is to study the influence of electroacupuncture "neiguan" on the p38MAPK signaling pathway in rats with cardiac hypertrophy, it has significant theoretical and practical value on the prevention and treatment of various causes of cardiac hypertrophy.
Methods
A total of503-month-old female SD rats,weighing about180g, were randomly divided into five groups by random number table method:the normal group, the model group, the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group, with ten rats in each group respectively.The rats in the normal group received3mg/kg·d physiologic saline injection into the back skin,and rats in the model group received3mg/kg·d isoprenaline hydrochloride for14days, the ECG changes:the duration of QRS wave and QT wave extended (QRS>0.10s), considering changes of T wave morphology as a sign of successful model, the electroacupuncture group received3mg/kg.d isoprenaline hydrochloride, the acupuncture needle were penetrated5mm into the bilateral "neiguan" acupoints and interconnected with a HANS electroacupuncture apparatus, in which the following stimulus parameters were selected:continuous-wave at2Hz and1mA, for20min every day, the P38MAPK inhibitor group were injected3mg/kg·d isoprenaline hydrochloride and0.3mg/kg/d SB203580, the electroacupuncture and P38MAPK inhibitor group injected3mg/kg·d isoprenaline hydrochloride and0.3mg/kg/d SB203580, were treated with electroacupuncture for14days. On the15th day,the body weights of the rats, as well as those of their left ventricle and the whole heart were recorded; then left ventricular weight index and the heart weight index were calculated. The heart tissue was done in hematoxylin-eosin staining, the average measurement of left ventricular wall thickness, the average diameter of the myocardial cell, the myocardial fiber diameter was measured, the content of NO in heart tissue and blood plasma were determined by the method of nitric acid reductase, the content of TNF-α and IL-1β in of heart tissue and blood plasma were measured by radioimmunoassay, the immune positive expression of p38MARK and p-p38MARK were detected by immunocytochemistry method, the p38MAPK and p-p38MAPK activity were determined by western blot, then analyzed the data through image analyse system and statistical analysis system.
Results
1. Compared with the normal group, HW, LVW, HWI, LVWI were significantly higher with statistical significance in model group (P<0.01); compared with the model group, HW, LVW, HWI, LVWI were significantly lower with statistical significance in the electroacupuncture group,the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05), but no significant difference between them(P>0.05).
2. Compared with the normal group, the average measurement of left ventricular wall thickness,the average diameter of the myocardial cell, the myocardial fiber diameter were significantly higher with statistical significance in model group (P<0.01), compared with the model group, the average measurement of left ventricular wall thickness,the average diameter of the myocardial cell, the myocardial fiber diameter were significantly lower with statistical significance in the electroacupuncture group,the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05, p<0.01), but no significant difference between them(P>0.05).
3. After staining of myocardial cells, the myocardial structure in normal group was clear, complete, uniform, and cardiac muscle fibers were arranged in neat rows, clear stripes,without morphological abnormalities;myocardial cells in model group were stained unevenly, cardiac muscle fibers was disordered, myocardial fiber diameter increased,the connective tissue among the myocardial fibers become loose,edema, hyperplasia,with the uneven size of cell,and cardiomyocyte diameter was significantly larger than that in normal group.After treatment, myocardial cells in the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group were slightly larger than that in model group,with acceptable arangement. Compared with the model group,cardiomyocyte hypertrophy was improved, myocardial fiber arrangement became neat, edema and hyperplasia were improved significantly.
4. Compared with the normal group, the content of NO in heart tissue and blood plasma were significantly lower with statistical significance in model group (P<0.01), compared with the model group, NO in heart tissue and blood plasma were significantly higher with statistical significance in the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05),but no significant difference between them(P>0.05).
5. Compared with the normal group, the content of TNF-α and IL-1β in heart tissue and blood plasma were significantly higher with statistical significance in model group (P<0.01), compared with the model group,TNF-α and IL-1β were significantly lower with statistical significance in the electroacupuncture group, the P38MAPK inhibitor group,the electroacupuncture and P38MAPK inhibitor group (P<0.05),but no significant difference between them(P>0.05).
6.Compared with the normal group, the immune positive expression of p38MAPK increased, the IOD of p38MAPK and p-p38MAPK were significantly higher with statistical significance in model group (P<0.01), compared with the model group, the IOD of p38MAPK was lower with statistical significance in the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05, p<0.01), but no significant difference between them(P>0.05).
7.Compared with the normal group,p38MAPK and p-p38MAPK in myocardial cells increased, was significantly higher in model group (P<0.01), compared with the model group, p38MAPK and p-p38MAPK in myocardial cells were lower with statistical significance in the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05, p< 0.01),but no significant difference between them(P>0.05).
Conclusion
1.Electroacupuncture at "neiguan" can decrease HWI and LVWI,the average measurement of left ventricular wall thickness, the average diameter of the myocardial cell,and the myocardial fiber diameter, and improve myocardial morphology significantly.
2. Electroacupuncture at "neiguan" can increase the content of NO in heart tissue and blood plasma, and prevent the myoeardial hypertrophy by improving the content of NO.
3. Electroacupuncture at "neiguan" acupoint can prevent the myoeardial hypertrophy through its anti-inflammation effect to adjust p38MAPK signaling pathway.
4. P38MAPK signaling pathway is involved in myoeardial hypertrophy caused by injected with isoprenaline hydrochloride, the up-regulation of expression of p38MARK promote the probability of cardiac hypertrophy occurrence, electroacupuncture at "Neiguan" may protect cardiac hypertrophy through regulating p38MAPK signaling pathway of myocardial cell.
5. There was no significant difference between the electroacu-puncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group. When electroacupuncture and P38MAPK inhibitor were added up,there was no additive effect, may be related to the strong inhibition of p38inhibitor of signaling pathways, the part effect of electroacupuncture at "Neiguan" is covered.
心肌肥厚是许多心血管疾病发展的一个重要阶段,在先天性心脏病、心肌梗死、心脏瓣膜病、高血压等多种心血管疾病中,心肌肥厚是共有的病理过程,持续的外界刺激引起心肌肥厚不断进展,使心肌氧耗量增加及顺应性降低,最终导致心脏扩大、充血性心力衰竭甚至猝死,是心血管疾病患病率和死亡率增加的独立危险因素,随着左室肥厚的发生、发展,猝死、室性心律失常、心肌缺血、心力衰竭等心血管事件的发生率增加6-10倍。药物等治疗取得了较好的疗效,但所带来的副作用和临床效应还需进一步验证,介入疗法虽然能改善患者的生活质量,然而作为有创性的治疗技术不可避免地会发生各种并发症,如血管迷走神经反射、血管内血栓形成、胸闷、胸痛,甚至导致死亡。因此,如何探明心肌肥厚发生机制,积极有效的防治心肌肥厚,减少心血管疾病病死率和发病率已成为国内外心血管领域研究热点和焦点。针灸作为低损伤的治疗方法在心脏病的防治中具有较好的疗效并且已广泛应用于临床。本课题在“心胸内关谋”经验总结和前期研究基础上,运用现代医学理论与实验方法研究电针“内关”对心肌肥厚大鼠心肌组织P38MAPK信号通路的影响及作用机制,对临床防治各种病因的心肌肥厚具有十分重要的理论意义和实用价值。
方法
3月龄雌性SD大鼠50只,体重180g左右,查随机数字表分为5组：正常组、模型组、电针组、p38抑制剂组、电针+p38抑制剂组,每组10只。正常组：每日颈背部皮下注射生理盐水3mg/kg·d；模型组：以IS03mg/kg·d颈背部皮下注射14d制备心肌肥厚模型,连续14天；以心电图的改变：QRS波和QT波持续时间延长(QRS>0.10s),T波形态改变作为造模成功的标志；电针组：每日颈背部皮下注射IS03.0mg/kg,针刺双侧“内关”深度约5mm,接HANS-200电针治疗仪,选用连续波,频率2Hz,强度为1mA,通电20min,1次／d,14d；p38抑制剂组：每日颈背部皮下注射IS03.0mg/kg, p38丝裂原激活蛋白激酶特异性抑制剂SB203580,以0.3mg/kg/d颈背部皮下注射,连续14d；电针+p38抑制剂组：每日颈背部皮下注射IS03.0mg/kg,SB203580以0.3mg/kg/d颈背部皮下注射,双侧“内关”穴接HANS-200电针治疗仪,选用连续波,频率2Hz,强度为1mA,通电20min,1次／d,14d。大鼠于第15天称取体重、左心室重量和全心重量,并计算左心室重量指数和全心重量指数,心肌组织HE染色,测量左心室壁平均厚度、心肌细胞平均直径、心肌纤维横径,硝酸还原酶法测定血清和心肌组织NO含量,放射免疫法检测血清和心肌组织TNF-α、IL-1β含量,免疫组织化学法检测心肌p38MAPK.p-p38MAPK免疫阳性细胞表达；蛋白质免疫印迹法检测p38MAPK.p-p38MAPK活性,运用图象分析系统进行检测,并对数据进行统计分析。
结果
1.模型组大鼠HW、LVW、HWI、LVWI于造模后升高,均明显高于正常组,有非常显著性差异义(p<0.01)；电针组、p38抑制剂组、电针+p38抑制剂组大鼠HW、LVW、HWI、LVWI均明显低于模型组,有显著性差异(p<0.05)；电针组、p38抑制剂组、电针+p38抑制剂组之间无显著性差异(p>0.05)。
2.模型组大鼠左心室壁平均厚度、心肌细胞平均直径、心肌纤维横径于造模后升高,和正常组比较,有非常显著性差异(p<0.01)；电针组、p38抑制剂组、电针+p38抑制剂组大鼠左心室壁平均厚度、心肌细胞平均直径、心肌纤维横径均明显低于模型组,和模型组比较有显著性差异(p<0.05),电针+p38抑制剂组和模型组比较,有非常显著性差异(p<0.01),三组之间比较无显著性差异(p>0.05)。
3.正常组心肌细胞染色后心肌结构清晰、完整、均匀,心肌纤维排列整齐,横纹清楚,无形态异常；模型组心肌细胞染色不均,心肌纤维走向紊乱,心肌纤维横径增加,心肌纤维之间的结缔组织疏松水肿、增生,细胞大小不均,心肌细胞直径明显变大,电针组、p38抑制剂组、电针+p38抑制剂组治疗后,心肌细胞稍大,排列尚可,心肌细胞肥厚程度较模型组减轻,心肌纤维排列稍整齐,水肿和增生明显改善。
4.模型组大鼠心肌组织和血清N0含量于造模后降低,均明显低于正常组,有非常显著性差异义(p<0.01)；电针组、p38抑制剂组、电针+p38抑制剂组大鼠NO均明显高于模型组,有显著性差异(p<0.05)；三组之间无显著性差异(p>0.05)
5.模型组大鼠心肌组织和血清TNF-α、IL-1β含量于造模后升高,和正常组比较,有非常显著性差异(p<0.01)；电针组、p38抑制剂组、电针+p38抑制剂组大鼠TNF-α、IL-1β含量均明显低于模型组,和模型组比较,有显著性差异(p<0.05),三组之间比较无显著性差异(p>0.05)。
6.造模后p38MAPK、p-p38MAPK免疫阳性物增多,平均积分光密度值明显高于正常组,和正常组比较,有非常显著性差异(p<0.01)；电针组、p38抑制剂组大鼠平均积分光密度值均明显低于模型组,和模型组比较,有显著性差异(p<0.05),电针+p38抑制剂组有非常显著性差异(p<0.01),三组之间比较无显著性差异(p>0.05)。
7.模型组大鼠心肌细胞p38MAPK、p-p38MAPK于造模后升高,和正常组比较,有非常显著性差异(p<0.01)；电针组、p38抑制剂组p38MAPK、 p-p38MAPK均明显低于模型组,有显著性差异(p<0.05),电针+p38抑制剂组和模型组比较有非常显著性差异(p<0.01),三组之间比较无显著性差异(p>0.05)
结论
1.电针“内关”穴可使心肌肥厚模型大鼠全心重量指数、左室重量指数下降,左心室壁平均厚度下降；心肌细胞平均直径和心肌纤维横径减小,对心肌形态学有明显改善。
2.电针“内关”穴可使心肌肥厚模型大鼠血清和心肌组织NO含量升高,其抗心肌肥厚作用可能是通过升高NO来实现的。
3.电针“内关”穴可以防治心肌肥厚,这种保护作用可能与抑制TNF-a、IL-1β等炎性因子的表达实现对p38MAPK信号通路调节有关。
4. P38MAPK信号转导通路参与异丙肾上腺致大鼠心肌肥厚过程,P38MAPK表达上调促进心肌肥厚发生,电针“内关”穴可以明显抑制心肌肥厚p38MAPK的磷酸化,对心肌细胞p38信号转导通路的调节可能是电针“内关”防治心肌肥厚的作用机制之一
5.电针、p38抑制剂、电针+p38抑制剂防治心肌肥厚结果比较并未见明显差异,电针+p38抑制剂并未出现叠加效应,可能与p38抑制剂对信号通路的抑制作用较强,掩盖了部分电针“内关”效应有关。
Objective
Cardiac hypertrophy is an important stage in the development of cardiovascular disease. In congenital heart disease, myocardial infarction,valvular heart disease, hypertension and other cardiovascular diseases,cardiac hypertrophy is a common pathological process. The continuous stimulation from outside causes the continuous progress of cardiac hypertrophy, it also increases the myocardial oxygen consumption and reduces compliance, eventually leads to cardiac enlargement, congestive heart failure and even sudden death,so it is an independent risk factor for the increasing cardiovascular disease morbidity and mortality. With the occurrence and development of left ventricular hypertrophy, sudden death, ventricular arrhythmia, myocardial ischemia, heart failure and other cardiovascular events rate increases by6-10times. Drug treatments achieve a good effect, but the side effects and clinical effects need further verification. Intervention therapy can improve the quality of life of patients, however,as an invasive treatment technology it will inevitably have a variety of complications, such as vasovagal reflex, vascular thrombosis,chest tightness, chest pain,or even leading to death. Therefore, finding out the function mechanism of cardiac hypertrophy, treating and preventing myocardial hypertrophy positive and effective, reducing cardiovascular disease mortality and morbidity rates have become the hot spots and focuses in the field of cardiovascular research all over the world. Acupuncture, as a low-injury treatment with good effect in the prevention and treatment of heart disease, has been widely used in cl inical. Guiding by the theory of Chinese acupuncture "for heart and chest, it is point Neiguan" and on the basis of preliminary studies,with modern medical theory and experimental methods,this experiment is to study the influence of electroacupuncture "neiguan" on the p38MAPK signaling pathway in rats with cardiac hypertrophy, it has significant theoretical and practical value on the prevention and treatment of various causes of cardiac hypertrophy.
Methods
A total of503-month-old female SD rats,weighing about180g, were randomly divided into five groups by random number table method:the normal group, the model group, the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group, with ten rats in each group respectively.The rats in the normal group received3mg/kg·d physiologic saline injection into the back skin,and rats in the model group received3mg/kg·d isoprenaline hydrochloride for14days, the ECG changes:the duration of QRS wave and QT wave extended (QRS>0.10s), considering changes of T wave morphology as a sign of successful model, the electroacupuncture group received3mg/kg.d isoprenaline hydrochloride, the acupuncture needle were penetrated5mm into the bilateral "neiguan" acupoints and interconnected with a HANS electroacupuncture apparatus, in which the following stimulus parameters were selected:continuous-wave at2Hz and1mA, for20min every day, the P38MAPK inhibitor group were injected3mg/kg·d isoprenaline hydrochloride and0.3mg/kg/d SB203580, the electroacupuncture and P38MAPK inhibitor group injected3mg/kg·d isoprenaline hydrochloride and0.3mg/kg/d SB203580, were treated with electroacupuncture for14days. On the15th day,the body weights of the rats, as well as those of their left ventricle and the whole heart were recorded; then left ventricular weight index and the heart weight index were calculated. The heart tissue was done in hematoxylin-eosin staining, the average measurement of left ventricular wall thickness, the average diameter of the myocardial cell, the myocardial fiber diameter was measured, the content of NO in heart tissue and blood plasma were determined by the method of nitric acid reductase, the content of TNF-α and IL-1β in of heart tissue and blood plasma were measured by radioimmunoassay, the immune positive expression of p38MARK and p-p38MARK were detected by immunocytochemistry method, the p38MAPK and p-p38MAPK activity were determined by western blot, then analyzed the data through image analyse system and statistical analysis system.
Results
1. Compared with the normal group, HW, LVW, HWI, LVWI were significantly higher with statistical significance in model group (P<0.01); compared with the model group, HW, LVW, HWI, LVWI were significantly lower with statistical significance in the electroacupuncture group,the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05), but no significant difference between them(P>0.05).
2. Compared with the normal group, the average measurement of left ventricular wall thickness,the average diameter of the myocardial cell, the myocardial fiber diameter were significantly higher with statistical significance in model group (P<0.01), compared with the model group, the average measurement of left ventricular wall thickness,the average diameter of the myocardial cell, the myocardial fiber diameter were significantly lower with statistical significance in the electroacupuncture group,the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05, p<0.01), but no significant difference between them(P>0.05).
3. After staining of myocardial cells, the myocardial structure in normal group was clear, complete, uniform, and cardiac muscle fibers were arranged in neat rows, clear stripes,without morphological abnormalities;myocardial cells in model group were stained unevenly, cardiac muscle fibers was disordered, myocardial fiber diameter increased,the connective tissue among the myocardial fibers become loose,edema, hyperplasia,with the uneven size of cell,and cardiomyocyte diameter was significantly larger than that in normal group.After treatment, myocardial cells in the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group were slightly larger than that in model group,with acceptable arangement. Compared with the model group,cardiomyocyte hypertrophy was improved, myocardial fiber arrangement became neat, edema and hyperplasia were improved significantly.
4. Compared with the normal group, the content of NO in heart tissue and blood plasma were significantly lower with statistical significance in model group (P<0.01), compared with the model group, NO in heart tissue and blood plasma were significantly higher with statistical significance in the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05),but no significant difference between them(P>0.05).
5. Compared with the normal group, the content of TNF-α and IL-1β in heart tissue and blood plasma were significantly higher with statistical significance in model group (P<0.01), compared with the model group,TNF-α and IL-1β were significantly lower with statistical significance in the electroacupuncture group, the P38MAPK inhibitor group,the electroacupuncture and P38MAPK inhibitor group (P<0.05),but no significant difference between them(P>0.05).
6.Compared with the normal group, the immune positive expression of p38MAPK increased, the IOD of p38MAPK and p-p38MAPK were significantly higher with statistical significance in model group (P<0.01), compared with the model group, the IOD of p38MAPK was lower with statistical significance in the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05, p<0.01), but no significant difference between them(P>0.05).
7.Compared with the normal group,p38MAPK and p-p38MAPK in myocardial cells increased, was significantly higher in model group (P<0.01), compared with the model group, p38MAPK and p-p38MAPK in myocardial cells were lower with statistical significance in the electroacupuncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group (P<0.05, p< 0.01),but no significant difference between them(P>0.05).
Conclusion
1.Electroacupuncture at "neiguan" can decrease HWI and LVWI,the average measurement of left ventricular wall thickness, the average diameter of the myocardial cell,and the myocardial fiber diameter, and improve myocardial morphology significantly.
2. Electroacupuncture at "neiguan" can increase the content of NO in heart tissue and blood plasma, and prevent the myoeardial hypertrophy by improving the content of NO.
3. Electroacupuncture at "neiguan" acupoint can prevent the myoeardial hypertrophy through its anti-inflammation effect to adjust p38MAPK signaling pathway.
4. P38MAPK signaling pathway is involved in myoeardial hypertrophy caused by injected with isoprenaline hydrochloride, the up-regulation of expression of p38MARK promote the probability of cardiac hypertrophy occurrence, electroacupuncture at "Neiguan" may protect cardiac hypertrophy through regulating p38MAPK signaling pathway of myocardial cell.
5. There was no significant difference between the electroacu-puncture group, the P38MAPK inhibitor group, the electroacupuncture and P38MAPK inhibitor group. When electroacupuncture and P38MAPK inhibitor were added up,there was no additive effect, may be related to the strong inhibition of p38inhibitor of signaling pathways, the part effect of electroacupuncture at "Neiguan" is covered.
引文
[1]李玲.心血管疾病的危险因素与干预策略[J].中华全科医学,2010,8(12)：1602-1604.
[2]中国高血压防治指南修订委员会.中国高血压防治指南(2005年修订版)[M].人民卫生出版社,2006.
[3]杨舟.心血管疾病危险因素的研究概况[J].内科,2008,3(2)：252.
[4]Hughes SE.The pathology of hypertrophic cardiomyopathy [J]. Histopathology,2004,44 (5):412-427.
[5]Bruckner BA, Razegh IP. Degree of cardiac f ibrosis and hypertrop-hy at time of implantation predicts myocardial improvement during left ventricular assist device support [J]. J Heart Lung T rans,2004, 23(1):36-42.
[6]何国新,符婵,戴德哉.治疗心肌肥厚药物的进展[J].中国新药杂志,2001,10(8)：576-579
[7]江珊,李玉霞,李彦.他汀类药物抗心肌肥厚的研究进展[J].心血管病学进展,2010,31(4)：588-590
[8]韩向东,陈长勋.中药防治心肌肥大的实验研究进展[J].时珍国医国药,2005,16(12)：1309-1312.
[9]张艳丽.心脏介入治疗常见不适及并发症的护理[J].中国现代药物应用,2008,2(22)：94.
[10]王霭平,潘怡静.针灸治疗冠心病的临床和实验研究进展[J].中国中医急症,2004,13(9)：615-616.
[11]严洁,杨孝芳,易受乡,等.电针“内关”对心肌缺血再灌注损伤大鼠心肌细胞膜钠泵活性及其基因表达的影响[J].针刺研究,2007,32(5)：296.
[12]林亚平,严洁,王超,等.电针内关对心肌缺血再灌注损伤大鼠cTnT及bax基因表达的影响[J].湖南中医学院学报,2006,26(2)：40.
[13]任路,马铁明,梁雪松,等.电针“内关”对缺血性心肌细胞热休克蛋白90表达影响的实验研究[J].中华中医药学刊,2007,25(3)：528.
[14]Frey N, Olson EN. Cardiac hypertrophy:the good, the bad and the ugly[J]. Annu RevPhysiol,2003,65:45-79.
[15]Ravingerova T, Barancik M, Strniskova M. Mitogen-activated pro-tein kinases:a new therapeutic target in cardiac pathology [J]. Mol Cell Biochem,2003,247 (1-2):127-138.
[16]Sugden PH. Signalling pathways in cardiac myocyte hypertrophy hypertrophy [J]. Ann Med,2001,33 (9):611-622.
[17]Hirotani S, Otsu K, Nishida K, et al. Involvement of nuclear fact-or-kappaB and apoptosis signal-regulating kinasel in G-protein coupled receptor agonist-induced cardiomyocyte ertrophy[J].Cir-culation,2002,105 (4):509-515.
[18]李向东,覃数.p38 MAPK在心肌肥厚中的作用机制[J].重庆医学,2007,36(14)：1438-1440.
[19]马文静,黄水清.p38丝裂原活化蛋白激酶在心血管疾病中的作用[J].中西医结合心脑血管病杂志,2008,6(7)：823-824.
[20]Loscalzo J,Welch G. Nitric oxide and its role in the cardiovasc-ular system[J]. Prog Cardiovasc Dis,1995,38:87.
[21]李伟,沈明勤,陆晓晖.中药防治心肌缺血再灌注损伤作用机制的研究进展[J].中华中医药杂志,2011,26(3)：549-553.
[22]吴松,唐宏图,陈泽斌,等. “双固一通”针法对急性心肌缺血模型大鼠心肌组织过氧化物酶活性的影响[J]. 湖北中医杂志2006;28(10)：3-5.
[23]尤行宏,王华,陈泽斌,等.延髓内阿片肽对电针抗心肌缺血效应的影响[J].现代中西医结合杂志,2009,18(29)：3541-3544.
[24]王华,涂乾,王亚文,等.电针内关穴抗家兔心肌缺血损伤下丘脑室旁核内阿片肽的作用[J].中国针灸,2005：25(10)：720-724.
[25]洪亚群,王华.“双固一通”针法对甲亢性心肌病大鼠心肌SOD、GSH-PX活性和MDA含量的影响[J].湖北中医学院学报,2006,8(2)：15-16.
[26]洪亚群,王华.“双固一通”针法对甲亢性心肌病大鼠心肌肥厚的保护作用[J].湖北中医杂志,2008,30(7)：5-6.
[1]Katz AM. The hypertrophic response:programmed cell death[M]. Heart Failure. Pathophysiology,Molecular Biology and Clinical Management. Baltimore, MD:Lippincott Williams & Wilkins,2000, 173-226.
[2]Wen Y, Peng Z, Jing HH, et al. Stimulation of κ-opioid receptor reduces isoprenalineinduced cardiac hypertrophy[J].European Journal of Pharmacology,2009,607 (1-3):135-142.
[3]E. Kra ova, T. Mokr a n, J. MurIn, et al. Electrocardiography in two models of isoproterenol-induced left ventricular remodeling [J].Physiol. Res.2008, (Suppl.2):S83-S89.
[4]王月兰,姚尚龙.丝裂原蛋白激酶信号转导通路在机械通气相关性肺损伤中的作用[J].中华实验外科杂志,2006,23(3)：331-333.
[5]Bos R,Mougenot N, Find j i L, etal. Inhibition of catecholamine induced cardiac f ibrosis by an aldosterone antagonist [J]. Cardiov-asc Pharmacol,2005,45(1):8-13.
[6]杨硕,杨孝芳,崔瑾,等.内关穴位埋针对心肌缺血小型猪心肌组织VEGF mRNA和蛋白表达的影响[J].中华中医药杂志,2011,26(4)：798-803.
[7]李万山,钟敏,杨进辉,等.电针“内关”穴预处理对缺血再灌注大鼠心肌阿片受体基因表达的影响[J].中国针灸,2011,31(5)：441-445.
[8]严洁,刁利红,易受乡,等.电针内关穴对心肌缺血再灌注损伤大鼠心肌能量代谢及组织形态学的影响[J].中国组织工程研究与临床康复,2007,11(47)：9443-9447.
[9]Gao J, Fu W, Jin Z, et al. Acupuncture pretreatment protectsheart from injury in rats with myocardial ischemia and reperfu-sion via inhibition of the β1-adrenoceptor signaling pathway [J]. Life Sci,2007,80(16):1484-1489.
[10]张江玲,陈杰,王祥瑞,等.电针“内关”穴预处理对缺血再灌注大鼠心肌的保护作用[J].针刺研究,2010,35(3)：182-187.
[1]Zhang P, Xu X, HU XL,et al. Inducible nitric oxide synthase deficiency protect the heats from systolic overload-induced ventricular hypertrophy and congestive heart failure[J].Cir Res, 2007.100(7):1089-1098.
[2]Wenzel S, Rohde C, Wingerning S, et al. Lack of endothelial nitric oxide synthase-derived nitric oxide formation favors hypertrophy in adult ventricular cardiomyocytes [J]. Hypertension,2007,49(1): 193-200
[3]Sun Y, Carretero OA, Xu J, et al. Lack of inducible NO synthaseredu-ces oxidative stress and enhances cardiac response to isoproterenol inmice with deoxycorticosterone acetatesalt hypertension[J]. Hypertension,2005,46(6):1355-1361.
[4]Koyanagi M, Egashira K, Kitamoto S, et al. Role of monocytechemoa-ttractant protein-1 in cardiovascular remodeling induced by chron-ic blockade of nitric oxide synthesis [J]. Circulation,2000,102 (18) :2243-2248.
[5]Loscalzo J, Welch G. Nitric oxide and its role in the cardiovascu-lar system[J].Prog Cardiovasc Dis,1995,38 (2):87-104.
[6]Kim NN, Villegas S, Summerour SR, et al. Regulation of cardiac fibrobl as text racel lular matrix production by bradykinin and ni tric oxide [J].J Mol Cell Cardiol.1999,31 (2):457-466.
[7]杨涛,张伟,张雷.L-精氨酸-一氧化氮途径对病理性心肌肥厚形成的抑制作用及相关机制[J].第二军医大学学报,2008,29(2)：177-183.
[8]钟南田,符史干,符皎荣,等.NO和Ang Ⅱ对大鼠心室重构影响的实验研究[J].中国临床解剖学杂志,2007,25(6)：669-673.
[9]Zhan CD. The role of nitricoxide in the prevention of myocardial hypertrophicresponse and its mechanisms [J]. Sheng Li Ke Xue Jin Zhan,2000,31(4):322-324.
[10]钟南田,符史干,符皎荣,等.一氧化氮在压力超负荷心肌肥大作用中的定量分析[J].解剖学杂志,2005,28(5)：517-519.
[11]李永胜.丹参酮ⅡA对腹主动脉缩窄高血压大鼠心肌肥厚的作用及分子生物学机制[D].华中科技大学,2007.
[12]苟怀宇,陈艳秋,黄晶,等.银杏叶提取物对异丙肾上腺素诱导的大鼠 心肌肥厚的影响.重庆医科大学学报,2010,35(2)：224-226.
[13]王超,田岳凤,周丹,等.电针“内关”穴对心肌缺血再灌注大鼠心肌组织一氧化氮、一氧化氮合酶和细胞内钙的影响[J].针刺研究,2010,35(2)：113-117.
[1]Shiota N, Rysa J. A role for cardiac mast cells in the pathogenesis of hypertensive heart disease[J]. Hypertens,2003,21(10):1935-1944
[2]Isoda K, Kamezawa Y, Tada N, et al. Myocardial hypertrophy in tran-sgenic mice overexpressing human interleukin-la[J]. Journal of Cardiac Failure,2001,3 (4):355-364.
[3]张雪娟,徐庆科,谭凯,等.阿托伐他汀防止压力负荷导致心肌肥厚的抗炎机制[J].中华高血压杂志,2008,16(11)：1028-1032.
[4]Woldback PR,sande JB,stromme TA.Daily administration of interleukin-18 cause mycardial dysfunetion inhealthy mice [J]. Am J Physiol Heart Circ Physiol,2005,289:708-714.
[5]Takeda K, Ichiki T, Narabayashi E, etal. Inhibition of Prolyl Hydr-oxylase domain-containing pretein suppressed lipopolysaccha-ride induced TNF-a expression [J]. Arterioscler Thromb Vase Biol,2009,29 (12):2132-2137.
[6]Lin J,Liliensiek B, Kanitz M, et al.Molecular cloning of genes differentially regulated by TNF-alpha in bovine aortic endothelial cells, fibroblasts and smooth muscle cells [J]. Cardiovasc Res,1998 38(3):802-813.
[7]Janczewski AM, Kadokami T, Lemster B, et al. Morphological and fun-ctional changes in cardiac myocytes isolated from mice overexpre-ssing TNF-alpha[J]. Am J Physiol Heart Circ Physiol,2003,284 (3): H960.
[8]Kuwahara F, Kai H, Tokuda K, et al. Roles of Intercel lular Adhesion Molecule-1 in Hypertensive Cardiac Remodeling[J]. Hypertension, 2003,41:819-823.
[9]Shioi T, Matsumor i A, Kihara Y, et al. Increased expression of int-erleukin-1β and monocyte chemotactic and activating factor Pmonocyte chemoattractant Protein-1 in the hypertrophied and failing heart with Pressure overload [J]. Circ Res,1997,81(5): 664-671.
[10]Harada E, Nakagawa 0, Yoshimura M, et al. Effect of interleukin-1 β on cardiac hypertrophy and production of natriuretic pep tides in rat cardiocyte culture [J]. Mol Cell Cardiol,1999,31 (11):1997-2006.
[1]FreyN,Olson E N.Cardiac hypertrophy:the good, the bad and the ugly[J]. Annu RevPhysiol,2003,65:45-79.
[2]李向东,覃数.p38 MAPK在心肌肥厚中的作用机制[J].重庆医学,2007,36(14)：1438-1440.
[3]马文静,黄水清.p38丝裂原活化蛋白激酶在心血管疾病中的作用[J].中西医结合心脑血管病杂志,2008,6(7)：823-824.
[4]Dony JS, Han JH. Cellular activation mechanisms in septic shock [J]. Frontiers in Bioscience,1998,30 (3):468-476.
[5]Kyriakis JM, Avruch J.Protein kinase cascades activated by str-ess and inflammatory cytokinesstress [J].Bioes says,1996,18 (7): 567-577.
[6]GumRJ,MeLaughlinMM, KumarS, etal. Acquisition of sensitivity of stress-activated Protein kinases to the P38 in hibitor, SB203580, by alter ation of one or more aminoaeids with in the ATP binding Poeket[J].J Biol Chem,1998,273 (25):15605-15610.
[7]Lisnock J,Tebben A, Frantz B, et al. Molecular basis for p38-protein kinase inhibitor specificity [J]. Biochemistry,1998,37 (47): 16573-16581.
[8]肖翔林,谭莹,陈文瑛,等.p38促丝裂原活化蛋白激酶对疾病调控作用的研究进展[J].中国药房,2007,18(8)：622-624.
[9]杜俊英,方剑乔,梁宜,等.p38MAPK通路参与炎性痛及电针干预的可能性[J].医学信息,2011,24(6)：3612-3613.
[10]万顺伦,孙锦平,李召峰.应激后大鼠下丘脑磷酸化P38MapK的变化及电针足三里穴的调节作用[J].中华物理医学与康复杂志,2005,27(4)：202-204.
[11]龚伟,王升旭.电针夹脊穴在佐剂性关节炎大鼠镇痛过程中磷酸化p38丝裂原活化蛋白激酶的变化及作用[J].中国临床康复,2004,8(8)：1514-1515.
[12]王航,黄浩,蔡克银.电针夹脊穴通过磷酸化p38 MAPK信号通路对大鼠炎性痛阈的影响[J].安徽中医学院学报,29(5)：34-37.
[1]戴文建,王以光.心肌肥厚分子机制研究进展[J].心血管病学进展,2009,30(1)： 47-51.
[2]Nakagami H, Takemoto M, Liao JK. NADPH oxidase-derived superoxide anion mediates angiotensin Ⅱ-induced cardiac hypertrophy [J].J Mol Cell Cardio,2003,35 (7):851-859.
[3]Johnson JA. An epsilon PKC-selective inhibitor attenuates back phosphorylation of a low molecular weight protein in cardiac myoc-ytes[J].Cell Signal,2003,15 (1):123-130.
[4]FreyN, Olson E N.Cardiac hypertrophy:the good, the bad and the ugly[J]. Annu RevPhysiol,2003,65:45-79.
[5]Sugden P H. Signalling pathways in cardiac myocyte hypertrophy [J]. Ann Med.2001,33 (9):611-622.
[6]Kaiser R A, Liang Q R, Bueno 0 F, et al. Genetic inhibition or acti-vation of JNK1/2 protects the myoccadium from ischemia reperfus-ion-induced cell death in vivo [J]. J Biol Chem,2005,280(38):32602-32608.
[7]Han J, Lee JD, Tobias PS,et al.Endotoxin induces rapid proteint-yrosine phosphorylation in 70Z/3 cells expressing CD14[J]. JBiol Chem,1993,268(33):25009-25014.
[8]Toshiyuki O,Glenn EB, Michael BY. MAP kinase pathways activated by stress:The p38 MAPK pathway [J]·CritCare Med,2000,28 (4):N67-N77.
[9]Tyler Zarubin, Han JH.Activation and signaling of the p38 MAP kinase pathway [J]. Cell Res,2005,15 (1):11-18.
[10]魏倩萍,邓华聪,赵劫.p38MAPK信号通路在大鼠肾小球系膜细胞表达VEGF中的作用[J].重庆医学,2005,34(1)：16-18.
[11]Schafer PH,Wsdsworth SA, Wang. L-p38mitogen-activated protein kinase is activated CD28-mediated signaling and is required for IL-4production by hum_an CD4+T cells and effector cells [J].J Immunol,1999,162 (12):7110-7119.
[12]Gum RJ, McLaughlin MM, Kumar S, etal. Acquisition of Sensitivity of Stress-activated Protein Kinases to the p38 Inhibitor, SB 203580, by Alteration of One or More Amino Acids within the ATP Binding Pocket [J].JBiol Chem.1998,273(25):15605-15610.
[13]Boyle DL, Jones TL, Hammaker D, etal. Regulation of peripheral inflammation byspinal p38 MAPkinase in rats [J]. Plos Med,2006,3 (9): e338.
[14]Fu H, Bylund J, Karlsson A, et al. The mechanism for activation of the neutrophilNADPH-oxidase by the peptides formyl-Met-Leu-Phe and Trp-Lys-Tyr-Met-Val-Metdiffers from that for interleukin-8 [J]. Immunology,2004,112 (2):201-210.
[15]Piao CS,Kim JB, Han PL, et al. Administration of the p38 MAPK inhibitorSB203580 affords brain protection with a wide the rapeutic window against focal ischemic insul [J]. Neurosci Res,2003,73 (4): 537-544.
[16]Goedert M, Cuenda A,Craxton M, et al.Activation of the novel stress-aetivated Protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6):comparison of its substrate specificity with that of other SAP kinases [J]. EMBOJ,1997,16:3563-3571.
[17]吴松,李佳,洪亚群,等.内关治疗心系疾病理论基础探析[J].辽宁中医杂志,2011,38(11)：2178-2179.
[18]刁利红,杨宗保,周国祥,等.电针内关穴为主治疗无症状心肌缺血疗效观察[J].中国针灸,2011,31(7)：591-594.
[19]刁利红,周国祥,陈燕,等.针刺内关穴为主对无症状心肌缺血患者 临床疗效以及血脂和血液流变学的影响[J].中华中医药学刊,2011,29(6)：1315-1317.
[20]李培润,王辉,高晶,等.针刺内关穴治疗低脉压综合征临床观察[J].中医杂志,2003,44(4)：262.
[21]唐波炎.针刺内关穴治疗快速性心律失常的即时疗效观察[D].广州中医药大学,2010.
[22]汪桐,泮群皖.内关-心脏短反射的实验研究[J].针刺研究,1991,(2)：115-119.
[23]陈树林,李育良. 内关、心俞与心脏相关的神经基础[J].中国针灸.1996；10(12)：33-35.
[24]夏冬冬,王湖冰,谷禾,等.内关穴形态学特征及其临床意义[J].中国针灸,2010,30(12)：1003-1006
[25]闫丽萍,汪榈.内关心脏短反射的双向效应及其联系途径的研究[J].上海针灸杂志,2000,19(3)：32-35
[26]Wang H,Zhang HH,Wu XP, etal.Effect of e lectroacupunc-ture at neiguan point on the content of beta-endorphin in medullary bulb of rabbits with acute myocardial ischemia [J]. Chinese Journal of Clinical Rehabilitation, 2004,21(8):4384-4385.
[27]李明磊,王华,陈泽斌.电针内关穴对AMI大鼠自主神经与中枢P物质、一氧化氮合酶的影响[J].中华中医药杂志,2007,22(8)：543-546.
[28]涂乾,王华,王亚文,等.下丘脑室旁核对电针内关穴抗急性心肌缺血损伤作用的影响[J].中医杂志,2006,47(9)：665-667.
[29]林亚平,易受乡,严洁,等.针刺内关对心肌缺血再灌注损伤家兔CGRP和PGE2的影响[J].中国中医药信息杂志,2003,10(8)：26-28.
[30]田岳凤,吴富东,乔海法,等.针刺手厥阴心包经穴对心肌缺血再灌注损伤肌钙蛋白T的影响[J].中国中西医结合急救杂志,2003,10(1)：3-5.
[31]王华,邓丽霞,吴绪平,等.电针“内关”对室性心动过速大鼠心率及血浆儿茶酚胺含量的影响[J].针刺研究,2009,34(3)：180-183.
[32]李万山,钟敏,杨进,等.电针“内关”穴预处理对缺血再灌注大鼠心肌阿片受体基因表达的影响[J].中国针灸,2011,31(5)：441-444.
[33]吴松,唐宏图,陈泽斌,等.“双固一通”针法对急性心肌缺血模型大鼠心肌组织过氧化物酶活性的影响[J],湖北中医杂志,2006,28(10)：3-5.
[34]严洁,杨孝芳,易受乡,等.电针“内关”对心肌缺血再灌注损伤大鼠心肌细胞膜钠泵活性及其基因表达的影响[J].针刺研究,2007,32(5)：296-300.
[35]林亚平,严洁,王超,等.电针内关对心肌缺血再灌注损伤大鼠cTnT及bax基因表达的影响[J].湖南中医学院学报,2006,26(2)：40-42.
[36]唐宏图,吴松,陈泽斌,等.“双固一通”针法对老年实验性急性心肌缺血模型大鼠Mg2+ATPase的影响[J].上海针灸杂志2006；(7)：45-48.
[37]陈泽斌,唐宏图,吴松,等.“双固一通”针法对心肌缺血模型大鼠心肌组织Ca2+-ATPase活性的影响[J].湖北中医杂志2005；27(9)：15-16.
[38]王超,田岳凤,周丹.电针“内关”穴对心肌缺血再灌注大鼠心肌组织一氧化氮、一氧化氮合酶和细胞内钙的影响[J].针刺研究,2010,35(2)：113-117.
[39]姚凤祯,王岩.针刺家兔内关穴对快速型心律失常模型心肌细胞离子通道影响的研究[J].中医药信息,2010,27(5)：90-93.
[40]黄日龙,张伟,东贵荣.电针内关穴对急性心肌缺血家兔心肌组织能量代谢的实验研究[J].针灸临床杂志,2010,26(12)：44-48.
[41]张雪莲.电针“内关”穴对失血性低血压大鼠心肌cAMP-PKA细胞信号转导通路的影响[D].辽宁中医药大学,2009.
[42]苏全德.电针内关、郄门对冠心病患者心电图效应的对比观察[D].山东中医药大学,2007.
[43]蔡荣林,胡玲,汪克明,等.电针“内关”“太冲”穴对急性心肌缺 血家兔心功能的影响[J].针刺研究,2010,35(2)：104-108.
[44]金鸿韵.针刺多经经穴对健康人胃、小肠、心电影响的差异分析[D].湖北中医药大学,2011.
[45]胡玲,蔡荣林,吴子建,等电针不同经穴对急性心肌缺血家兔心功能的影响[J].针刺研究,2008,33(2)：88-93.
[46]王超,田岳凤,周丹.电针“内关”穴对心肌缺血再灌注大鼠心肌组织一氧化氮、一氧化氮合酶和细胞内钙的影响[J].针刺研究,2010,35(2)：113-117.
[47]李峰,冯耀光.大鼠心肌肥厚模型概述[J].中国现代医生,2011,48(32)：6-11
[48]王月兰,姚尚龙.丝裂原蛋白激酶信号转导通路在机械通气相关性肺损伤中的作用[J].中华实验外科杂志,2006,23(3)：331-333.
[49]鲁伟,刘培庆,王庭槐,等.MAPK信号途径在一氧化氮抑制大鼠心肌肥大中的作用.生理学报,2001,53(1)：32-36.
[50]Fi jen JW, Zi jlstra JG, De Boer P, et al. Suppression of the clinic-al and cytokineresponse to endotoxin by RWJ-67657,a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers [J] Clin Exp Immunol.2001,124(1):16-20.
[51]Liu H,Nishitoh H, Ichijo H, et al. Activation of apoptosis signal-regulating kinasel (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin[J]. Mol Cell Biol,2000,20 (6):2198-2208.
[52]Chen CC,Sun YT, ChenJJ,etal. Tumor necrosis factor-α-induced cyclooxygenase-2 expression via sequential activation of ceramide-dependent mitogenactivated protein kinase, and IkB kinase 1/2 in human alveolar epithelial cells [J]. Molpharmacol,2001,59 (3):493-500.
[53]McDermott E P,0 Neill L A.Ras participates in the activation of p38 MAPK byinterleukin-1 by associating with IRAK, IRAK2, TRAF6 and TAK-1[J].J Biol Chem,2002,277 (10):7808-7815.
[54]Perregaux DG, Dean D, Cronan M, et al. Inhibition of interleukin-1 beta production bySKF86002:evidence of two sites of in vitro activity and of a time and systemdependence [J]. Mol Pharmacol,1995, 48:433-442.
[1]Hughes SE.The pathology of hypertrophic cardiomyopathy [J]. Histopathology,2004,44 (5):412-427.
[2]Hirotani S, Otsu K, Nishida K, et al. Involvement of nuclear factor kappaB and apoptosis signal-regulating kinasel in G-protein coup-led receptor agonist-induced cardiomyocyte ertrophy[J]. Circula-tion,2002,105 (4):509-515.
[3]Han J, Lee JD, Tobias PS, et al. Endotoxin induces rapid proteint-yrosine phosphorylation in 70Z/3 cells expressing CD14[J]. Jbiol Chem,1993,268 (33):25009-25014.
[4]孙红霞.依那普利抗心肌纤维化作用及分子机制研究[D].吉林大学,2008.
[5]Toshiyuki 0, Glenn EB, Michael BY. MAP Kinase pathwaysactivated by stress:the p38MAPK pathway [J]. CritCare Med,2000,28 (4):67-77.
[6]Tyler Zarubin, Han JH. Activation and signaling of the p38 MAP kinase pathway [J]. Cell Res,2005,15 (1):11-18.
[7]Raingeaud J, Whitmarsh AJ, Barrett T, etal.MKK3 and MKK6 regulat-ed gene expression is mediated by the p38 mitogen activatedprote in kinase signal transduction pathway [J]. Mol Cell Biol,1996,16 (3): 1247-1255.
[8]Schafer PH, Wsdsworth SA, Wang L. p38a mi togen-act ivated prote-in kinase is activated CD28-mediated signaling and is required for IL-4 product ion by human CD4+ Tcells and effector cells [J]. J Immu-nol,1999,162 (12):7110-7119.
[9]GumRJ,MeLaughlinMM, KumarS, etal. A equisition of sensitivity of stress-activated Protein kinases to the P38 inhibitor, SB203580, by alter ation of one or more aminoaeids with in the ATP binding Poeket[J]. JB101 Chem,1998,273 (25):15605-15610.
[10]Boyle DL,Jones TL, Hammaker D, et al. Regulation of peripheral inflammation byspinal p38 MAPkinase in rats [J]. PloS Med,2006,3(9): e338.
[11]Fu H, Bylund J,Karlsson A, et al.The mechanism for activation of the neutrophilNADPH-oxidase by the peptides formyl-Met-Leu-Phe and Trp-Lys-Tyr-Met-Val-Metdiffers from that for interleukin-8 [J]. Immunology,2004,112 (2):201-210.
[12]Piao CS,Kim JB, Han PL, et al. Administration of the p38 MAPK inhibitorSB203580 affords brain protection with a wide the rapeutic window against focal ischemic insul [J]. Neurosci Res,2003,73 (4): 537-544.
[13]Goedert M, Cuenda A, Craxton M, et al. Activation of the novel stress-aetivated Protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6):comparison of its substrate specificity with that of other SAP kinases[J]. EMBOJ,1997,16: 3563-3571.
[14]Ritchie RH,Delbridge LMD. Cardiac hypertrophy, substrate uti-lization and metabolic remodelling:cause or effect[J]. Clin Exp Pharmacol Physiol,2006,33 (1-2):159-166
[15]Tsujimoto I, Hikoso S, Yamaguchi 0, et al. The antioxidant edara-vone attenuates pressure overload-induced leftventricular hyper-trophy [J]. Hypertension,2005,45 (5):921-926.
[16]Cheng TH, Shih NL, Chen CH, et al.Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chaingene expression and cardiomyocyte hypertrophy [J]. J Biomed Sci,2005,12 (1):123-133.
[17]Braz JC, Bueno OF, Liang Q, et al. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathythrough upregulation of calcineurin-NFAT signaling [J]. JClin Invest,2003,111 (10):1475-148 6.
[18]Pu L,Dimitrios G, Attila K. The in vivo role of p38MAPkinases in cardiac remodeling and restrictive cardiomyopa-thy [J]. Proc Natl Acad Sci USA,2001,98 (21):12283-12288.
[19]See F, Thomas W, Way K, et al. p38 mitogen-activatedprotein kin-ase inhibition improves cardiac function and at-tenuates left ventricular remodeling following myocardialinfarction in the rat[J].J Am Coll Cardiol,2004,44 (8):1679-1689.
[20]Matsumoto M, Takimoto Y, Aoyama T, et al. Activation of TGF-betal-TAK1-p38 MAPK pathway in spared cardiomyocytes isinvolved in left ventricular remodeling after myocardial infarction in rats [J].Am J Physiol Heart Circ Physiol,2006,290 (2):709-715.
[21]Zhang D,Gaussin V,Taffet GE, et al. TAK1 is activatedin the myocardium after pressure overload and is suffi-cient to provoke heart failure in transgenic mice[J].Nat Med,2000,6 (5):556-563.
[22]李向东,覃数.p38 MAPK在心肌肥厚中的作用机制[J].重庆医学,2007,36(14)：1438-1440.
[1]张云飞,吴先均,文秀华,等.心肌肥厚机制研究进展[J].心血管病学进展,2005,26(2)：197-200.
[2]陈修,陈维洲,曾贵云.心血管药理学[M](第三版).人民卫生出版社,2002.
[3]张明国,李雪峰.细胞调亡在心血管病中的研究[J].医学综述,2004,10(8)：470-472.
[4]Motoaki Sano,Keiichi Fukuda,Toshiniko Sato. ERK and p38MAPK, but not NF-KB, are criticallly involved in reactive oxygen species-mediated induction of IL-6 by angiotensinⅡ in cardiac fibroblasts [J]. CircRes,2001,89 (8):661-669.
[5]Henry E Kim, Seema S Dalal, Erik Young. Disruption of the myocardi-al extracellular matrix leads to cardiac dysfunction[J]. J Clin Invest,2000,106 (7):857-866.
[6]Aoki H, RichmondM, Izumo S et al. Specific role of the extracel lu-lar-signal-regulated kinase pathway in Angiotensin Ⅱ-in-duced cardiac hypertrophy in vitro [J]. Biochem J,2000,347(1):275-284.
[7]George W Booz, Jonathan N E Day, Kenneth M Baker. Interplay between the cardiac rennin angiotensin system and JAK-STAT signaling:role in cardiac hypertrophy, ischemia/repefusion dysfunction, and heart failure[J].J Mol Cell Cardiol,2002,34 (11):1443-1453.
[8]殷仁富,陈金明.心脏能量学[M].第二军医大学出版社,2002.
[9]Wang X, Dhalla NS. Modification of beta-adrenoceptor signal tra-nsduction pathway by geneticmanipulation and heart failure [J]. Mol Cell Biochem,2000,214(1-2):131-15.
[10]金惠铭,卢建,殷莲华.细胞分子病理生理学[M].郑州大学出版社,2002.
[11]Zhao XS, Pan WT, Raffi B, etal. Endogenous endothel in-1 is requir-ed forcardiomyocyte survival in vivo[J]. Circulation,2006,114: 830-837.
[12]油红文,陈曦,油红捷,等.内皮素及其受体对心脏细胞肥大与增殖的作用[J].中国医学科学院学报,2006；28(4)：520-523.
[13]Nobutake S, Subrina J, SohelZ, etal. Eicosapentaenoic acid prev-ents endothelin-1-induced cardiomyocyte hypertrophy in vitro through the suppression of TGF-β1 and phosphorylated JNK [J]. Am J Physiol Heart Circ Physiol 2006,291 (2):H835-H845.
[14]Zhu W, Zou Y, Shio j ima I, et al. Ca2+/calmodul in-dependent kinase II and calcineurin play critical roles in endothelin-1-induced cardiomyocyte hypertrophy [J]. J Biol Chem,2000,275 (20):15239-1524 5.
[15]Tanaka K,Honda M, Takabatake T. Redox regulation of MAPK path-ways and cardiac hypertrophy in adult rat cardiac myocyte[J].J Am Coll Cardiol,2001,37 (2):676-685.
[16]Wang YZ,Luo JD,Liu XH.Simvastain inhibits ROS mediated the neonatal rat cardiacmyocyte hypertrophy induced by endothelin-1 [Jl.Chin Pharmacol Bull,2003,19 (8):871-875.
[17]Zhan CD. The role of nitricoxide in the prevention of myocardial hypertrophicresponse and its mechanisms[J]. Sheng Li Ke Xue Jin Zhan,2000,31(4):322-324.
[18]Harada E, Yoshimura M, Yasue H, et al. Aldostrone induces angiote-nsin converting-enzyme gene expression in cultured neonatal ratcardiocytes [J]. Circulation,2001,104 (2):137-139.
[19]Takeda Y, Yoneda T, Demura M, et al. Calcineurin inhibition atten-uates mineralocorticoid-induced cardiac hypertrophy[J]. Circulat-ion,2002,105 (6):677-679.
[20]李凌峰,陈良万.心肌肥厚发生机制研究[J].海南医学,2008,19(7)：123-125.
[21]Knowles JW, Esposito G, Mao L, etal. Pressure-independent enhan-cement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice[J].J Clin Invest,2001,107 (8):975-984.
[22]刘洪梅,刘彤,黄体钢.高血压左室肥厚兔心房利钠肽水平和左房直径的变化[J].陕西医学杂志,2008,37(4)：405-407.
[23]马晓庆,苏胜偶.内皮素、血管紧张素Ⅱ、转化生长因子β1与心肌肥厚关系的研究进展[J].中国老年学杂志,2009,29(6)：766-768.
[24]BaudinoTA, CarverW, GilesW, et al. Cardiac fibroblasts:friend or foe [J]. Am J PhysiolHeartCirc Physiol,2006,291 (3):1015-1026.
[25]谢亚芹,周青云,康大伟.TGF-β1与慢性心力衰竭大鼠心肌肥厚的关系[J].中国老年学杂志,2011,31(7)：1183-1187.
[26]李永胜,严丽,雍永权.丹参酮ⅡA对高血压大鼠肥厚心肌TGF-β 1/Smads信号通路的影响[J].中国中西医结合杂志,2010,30(5)：499-504.
[27]Rosenkranz S, FleschM, Bohm M, et al. Alterations of beta-adrene-rgic signaling and cardiac hypertrophy in transgenicmice overexpr-essing TGF-beta(1) [J]. Am J Physiol Heart Circ Physiol,2002,283 (3): 1253-1262.
[28]罗惠兰,何作云,冯兵,等.人心肌肥大时碱性成纤维细胞生长因子和转化生长因子表达的变化及其意义[J].中华心血管病杂志,2001,29(7)：402-406.
[29]Cittadini A, Stromer H, Katz SE, et al. Differential cardiac effe-cts ofgrowth hormone and insulin-like growth factor-1 in the rat:a combined in vivo and in vitro evaluation [J]. Circulation,1996,93 (4):800-809.
[30]黄顺伟,唐可京,高修仁.原发性高血压合并心肌肥厚与胰岛素样生长因子-1的关系研究[J].中国循环杂志,2004,19(3)：202-204.
[31]Weismuller T, KLEIN J, Loffelholz K. Effects of norepinephrine and cardiotrophin-1 on phospholi-pase dactivity and incorporation of myristic acidinto phosphatidylcholine in rat heart [J]. J Pharma-co Sci,2004,95 (3):335-340.
[32]Jougasaki M, Tachibana I, Luchner A, et al. Augmented cardiac cardiotrophin-1 in experimental congestive heart failure [J].Cir culation,2000,101(1):14-17.
[33]Shioi T,Matsumori AKihara Y, et al. Increased expression of interleukin-1 β and monocyte chemotactic and activating factor Pmonocyte chemoattractant Protein-1 in the hypertrophied and failing heart with Pressure overload [J]. Circ Res,1997,81(5): 664-671.
[34]Harada E, Nakagawa O, Yoshimura M, et al. Effect of interleukin-1 (3 on cardiac hypertrophy and production of natriuretic peptides in rat cardiocyte culture [J]. Mol Cell Cardiol,1999,31 (11):1997-2006.
[35]Janczewski AM,Kadokami T,Lemster B,et al.Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alPha[J]. Am J Physiol Heart Circ Physiol,2003, 284 (3):H960.
[36]Liu H, Ni shit oh H, Ichi jo H, et al. Activation of apoptosis signal regulating kinasel (ASK1) by tumor necrosis factor receptor associa-ted factor2 requires prior dissociationof the ASK1 inhibitor thioredoxin[J].MolCell Biol,2000,20 (6):2198-2208.
[37]Chen CC,Sun YT,ChenJJ,et al. Tumor necrosis factor a induced cyclooxygenase-2 expression via sequential activation of ceramide-dependent mitogenactivated protein kinase, and IkB kinase1/2 in human alveolar epithelial cells [J]. Molpharmacol,2001,59(3):493-500.
[38]Me Dermott EP,O Neill LA. Ras participates in the activation of p38 MAPK byinterleukin-1 by associating with IRAK, IRAK2, TRAF6 and TAK-1[J].J Biol Chem,2002,277 (10):7808-7815.
[39]黄政德,李鑫辉,谢雪姣,等.活血化瘀药对血瘀证心肌缺血再灌注损伤家兔内源性活性因子及炎症因子的影响[J].中华中医药学刊,2007,25(7)： 1319-1321.
[40]戴文建,王以光.心肌肥厚分子机制研究进展….心血管病学进展,2009,30(1)：47-51.
[41]Nakagami H, Takemoto M, Liao JK. NADPH oxidase-derived superox-ide an ion mediates angiotensin Ⅱ-induced cardiac hypertrophy [J]. J Mol Cell Cardio,2003,35(7):851-859.
[42]Johnson JA. An PKC-selective inhibitor attenuates back phosph-orylation of a low molecular weight protein in cardiac myocytes [J].Cell Signal,2003,15:123-130.
[43]Frey N, Olson EN. Cardiac hypertrophy:the good, the bad and the ugly[J]. Annu RevPhysiol,2003,65:45-79.
[44]Sugden P H. Signalling pathways in cardiac myocyte hypertrophy [J]. Ann Med.2001,33 (9):611-622.
[45]Kaiser RA, Liang QR, Bueno OF, et al. Genetic inhibition or activ-ation of JNK1/2 protects the myoccadium from ischemia reperfusion-induced cell death in vivo[J]. J Biol Chem,2005,280 (38):32602-3260 8.
[46]Manning G, Whyte DB,Martinez R, et al. The protein kinase comple-ment of the human genome [J]. Science,2002,298 (5600):1912-1934.
[47]Widmann C, Gibson S, Jarpe MB, et al. Mitogen-activated protein kinase:congservation of a three-kinase module from yeast to human[J]. Physiol Rev1999,79 (1):143-180.
[48]Tori is, Nakayama K, Yamamoto T, et al. Regulatory mechanisms function of ERK MAP kinases[J].J Riochem,2004,136 (5):557-561.
[49]Sebolt-Leopold JS,Herrera R.Targeting the mitogen-activated protein kinase cascade to treat cancer[J]. Nat Rev Cancer,2004,4 (12):937-947.
[50]Haq S, Choukroun G,Lim H, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure [J]. Circulation.2001,103 (5):670-677.
[51]Wang L, Proud CG. Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes [J].Circ. Res.2002,91 (9):821-829.
[52]王祥,戴友平,杨杪,等.心房颤动心房组织内细胞外信号调节激酶和血管紧张素转化酶表达的研究[J].中华心血管病杂志,2004,32(3)：207-210.
[53]Davis RJ.Signal transduction by the JNK group of MAPkinases [J]. Cell,2000,103 (2):239-252.
[54]Sugden PH. Signalling pathways in cardiac myocyte hypertrophy [J].Ann Med 2001; 33 (9):611-622.
[55]Frazier D P, Wilson A, Dongherty C J, et al. PKC-alpha and TAK-1 are interm ediates in the activation of c—Jun NH2. terminal kinase by hypoxia—reoxygenation[J]. Am J Physiol Heart Circ Physiol,2007, 292 (4):1675-1684.
[56]Kaiser RA, Liang QR, Bueno OF, et al. Genetic inhibition or acti-vation of JNK1/2 protects the myoccadium from ischemia reperfusion-induced cell death in vivo [J]. J Biol Chem,2005,280(38):32602-3 2608.
[57]Martindale JL, Holbrook NJ. Cellular response to oxidative stress:signaling for suicide and survival [J]. J Cell Physiol,2002, 192(1):1-15.
[58]Nemoto S, Sheng Z, Lin A. Opposing effects of Jun kinase and P38 mitogen activated protein kinases on caridomyocyte hypertrophy [J].Mol Cell Biol,1998,18 (6):3518-3126.
[59]Toshiyuki 0, Glenn EB, Michael BY. MAP Kinase pathwaysactivated by stress:the p38MAPK pathway [J]. CritCare Med,2000,28 (4):67-77.
[60]Tyler Zarubin, Han JH. Activation and signaling of the p38 MAP kinase pathway [J]. Cell Res,2005,15 (1):11-18.
[61]魏倩萍,邓华聪,赵劫.p38MAPK信号通路在大鼠肾小球系膜细胞表达VEGF中的作用[J].重庆医学,2005,34(1)：16-18.
[62]Vallentin A,Mochly-Rosen D.RBCK1,a protein kinase Cbetal (PKCbetaI)-interacting protein, regulates PKC beta-dependent func-tion [J].J Biol Chem,2007,282 (3):1650-1657.
[63]刘丽娜,李法琦.心肌肥厚相关信号通路的研究进展[J].重庆医学2010,39(20)：2805-2808.
[64]王曙霞,惠汝太.心肌肥厚信号传导通路的研究进展[J].中国分子心脏病学杂志,2006,6(6)：363—368.
[65]WANG PY, LIU J,XU SM, et al. Nuclear Ca2+ transport of isoprenali-ne induced heart hypertrophy in rats[J]. Chinese Journal of pharmacology and Toxicology,2002,16 (1):25-30.
[66]谭建新,陈新民,王优,等.钙调神经磷酸酶信号通路介导大鼠慢性缺氧性右心室心肌肥厚[J].实用儿科临床杂志,2008,23(13)：1002-1004.
[67]Muth JN. Bodi I. Lewis W, et al. A Ca2+-dependent transgenic model of cardiachypertrophy:A role for protein kinase Calpha[J]. Circulation.2001,103(1):140-147.
[68]Morisco C,Zebrowski D,Condorelli B, et al.The Akt-glycogen synthase kinase3beta pathway regulates transcription of arrial natriuretic factor induced bybeta-adrenergic receptor stimulation in cardiac myocytes [J]. J Biol Chem,2000,275 (19):14466-14475.
[69]Shiojima I,Walsh K.Regulation ofcardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway [J]. GenesDev,2006,20 (24):3347-3365.
[70]Condorelli G, Drusco A, Stassi G, et al.Akt induces enhanced myocardial contractility and cell size in vivo in transgenicmice [J].Proc Natl Acad Sci USA,2002,99 (19):12333-12338.
[71]穆灵敏,王文锋,郭志坤,等.PI3K Akt蛋白在异丙肾上腺素所致大鼠心肌肥厚中的表达[J].四川动物,2010,29(4)：560-563.
[72]Kunisada K, Negoro S, Tone E, et al. Signal transducer and activa-tor of transcription3 in the heart transduces not only a hypertroph-ic signal but a protective signal against doxorubicin-induced cardiomyopathy[J].Natl Acad Sci USA,2000,97 (1):315-319.
[2]中国高血压防治指南修订委员会.中国高血压防治指南(2005年修订版)[M].人民卫生出版社,2006.
[3]杨舟.心血管疾病危险因素的研究概况[J].内科,2008,3(2)：252.
[4]Hughes SE.The pathology of hypertrophic cardiomyopathy [J]. Histopathology,2004,44 (5):412-427.
[5]Bruckner BA, Razegh IP. Degree of cardiac f ibrosis and hypertrop-hy at time of implantation predicts myocardial improvement during left ventricular assist device support [J]. J Heart Lung T rans,2004, 23(1):36-42.
[6]何国新,符婵,戴德哉.治疗心肌肥厚药物的进展[J].中国新药杂志,2001,10(8)：576-579
[7]江珊,李玉霞,李彦.他汀类药物抗心肌肥厚的研究进展[J].心血管病学进展,2010,31(4)：588-590
[8]韩向东,陈长勋.中药防治心肌肥大的实验研究进展[J].时珍国医国药,2005,16(12)：1309-1312.
[9]张艳丽.心脏介入治疗常见不适及并发症的护理[J].中国现代药物应用,2008,2(22)：94.
[10]王霭平,潘怡静.针灸治疗冠心病的临床和实验研究进展[J].中国中医急症,2004,13(9)：615-616.
[11]严洁,杨孝芳,易受乡,等.电针“内关”对心肌缺血再灌注损伤大鼠心肌细胞膜钠泵活性及其基因表达的影响[J].针刺研究,2007,32(5)：296.
[12]林亚平,严洁,王超,等.电针内关对心肌缺血再灌注损伤大鼠cTnT及bax基因表达的影响[J].湖南中医学院学报,2006,26(2)：40.
[13]任路,马铁明,梁雪松,等.电针“内关”对缺血性心肌细胞热休克蛋白90表达影响的实验研究[J].中华中医药学刊,2007,25(3)：528.
[14]Frey N, Olson EN. Cardiac hypertrophy:the good, the bad and the ugly[J]. Annu RevPhysiol,2003,65:45-79.
[15]Ravingerova T, Barancik M, Strniskova M. Mitogen-activated pro-tein kinases:a new therapeutic target in cardiac pathology [J]. Mol Cell Biochem,2003,247 (1-2):127-138.
[16]Sugden PH. Signalling pathways in cardiac myocyte hypertrophy hypertrophy [J]. Ann Med,2001,33 (9):611-622.
[17]Hirotani S, Otsu K, Nishida K, et al. Involvement of nuclear fact-or-kappaB and apoptosis signal-regulating kinasel in G-protein coupled receptor agonist-induced cardiomyocyte ertrophy[J].Cir-culation,2002,105 (4):509-515.
[18]李向东,覃数.p38 MAPK在心肌肥厚中的作用机制[J].重庆医学,2007,36(14)：1438-1440.
[19]马文静,黄水清.p38丝裂原活化蛋白激酶在心血管疾病中的作用[J].中西医结合心脑血管病杂志,2008,6(7)：823-824.
[20]Loscalzo J,Welch G. Nitric oxide and its role in the cardiovasc-ular system[J]. Prog Cardiovasc Dis,1995,38:87.
[21]李伟,沈明勤,陆晓晖.中药防治心肌缺血再灌注损伤作用机制的研究进展[J].中华中医药杂志,2011,26(3)：549-553.
[22]吴松,唐宏图,陈泽斌,等. “双固一通”针法对急性心肌缺血模型大鼠心肌组织过氧化物酶活性的影响[J]. 湖北中医杂志2006;28(10)：3-5.
[23]尤行宏,王华,陈泽斌,等.延髓内阿片肽对电针抗心肌缺血效应的影响[J].现代中西医结合杂志,2009,18(29)：3541-3544.
[24]王华,涂乾,王亚文,等.电针内关穴抗家兔心肌缺血损伤下丘脑室旁核内阿片肽的作用[J].中国针灸,2005：25(10)：720-724.
[25]洪亚群,王华.“双固一通”针法对甲亢性心肌病大鼠心肌SOD、GSH-PX活性和MDA含量的影响[J].湖北中医学院学报,2006,8(2)：15-16.
[26]洪亚群,王华.“双固一通”针法对甲亢性心肌病大鼠心肌肥厚的保护作用[J].湖北中医杂志,2008,30(7)：5-6.
[1]Katz AM. The hypertrophic response:programmed cell death[M]. Heart Failure. Pathophysiology,Molecular Biology and Clinical Management. Baltimore, MD:Lippincott Williams & Wilkins,2000, 173-226.
[2]Wen Y, Peng Z, Jing HH, et al. Stimulation of κ-opioid receptor reduces isoprenalineinduced cardiac hypertrophy[J].European Journal of Pharmacology,2009,607 (1-3):135-142.
[3]E. Kra ova, T. Mokr a n, J. MurIn, et al. Electrocardiography in two models of isoproterenol-induced left ventricular remodeling [J].Physiol. Res.2008, (Suppl.2):S83-S89.
[4]王月兰,姚尚龙.丝裂原蛋白激酶信号转导通路在机械通气相关性肺损伤中的作用[J].中华实验外科杂志,2006,23(3)：331-333.
[5]Bos R,Mougenot N, Find j i L, etal. Inhibition of catecholamine induced cardiac f ibrosis by an aldosterone antagonist [J]. Cardiov-asc Pharmacol,2005,45(1):8-13.
[6]杨硕,杨孝芳,崔瑾,等.内关穴位埋针对心肌缺血小型猪心肌组织VEGF mRNA和蛋白表达的影响[J].中华中医药杂志,2011,26(4)：798-803.
[7]李万山,钟敏,杨进辉,等.电针“内关”穴预处理对缺血再灌注大鼠心肌阿片受体基因表达的影响[J].中国针灸,2011,31(5)：441-445.
[8]严洁,刁利红,易受乡,等.电针内关穴对心肌缺血再灌注损伤大鼠心肌能量代谢及组织形态学的影响[J].中国组织工程研究与临床康复,2007,11(47)：9443-9447.
[9]Gao J, Fu W, Jin Z, et al. Acupuncture pretreatment protectsheart from injury in rats with myocardial ischemia and reperfu-sion via inhibition of the β1-adrenoceptor signaling pathway [J]. Life Sci,2007,80(16):1484-1489.
[10]张江玲,陈杰,王祥瑞,等.电针“内关”穴预处理对缺血再灌注大鼠心肌的保护作用[J].针刺研究,2010,35(3)：182-187.
[1]Zhang P, Xu X, HU XL,et al. Inducible nitric oxide synthase deficiency protect the heats from systolic overload-induced ventricular hypertrophy and congestive heart failure[J].Cir Res, 2007.100(7):1089-1098.
[2]Wenzel S, Rohde C, Wingerning S, et al. Lack of endothelial nitric oxide synthase-derived nitric oxide formation favors hypertrophy in adult ventricular cardiomyocytes [J]. Hypertension,2007,49(1): 193-200
[3]Sun Y, Carretero OA, Xu J, et al. Lack of inducible NO synthaseredu-ces oxidative stress and enhances cardiac response to isoproterenol inmice with deoxycorticosterone acetatesalt hypertension[J]. Hypertension,2005,46(6):1355-1361.
[4]Koyanagi M, Egashira K, Kitamoto S, et al. Role of monocytechemoa-ttractant protein-1 in cardiovascular remodeling induced by chron-ic blockade of nitric oxide synthesis [J]. Circulation,2000,102 (18) :2243-2248.
[5]Loscalzo J, Welch G. Nitric oxide and its role in the cardiovascu-lar system[J].Prog Cardiovasc Dis,1995,38 (2):87-104.
[6]Kim NN, Villegas S, Summerour SR, et al. Regulation of cardiac fibrobl as text racel lular matrix production by bradykinin and ni tric oxide [J].J Mol Cell Cardiol.1999,31 (2):457-466.
[7]杨涛,张伟,张雷.L-精氨酸-一氧化氮途径对病理性心肌肥厚形成的抑制作用及相关机制[J].第二军医大学学报,2008,29(2)：177-183.
[8]钟南田,符史干,符皎荣,等.NO和Ang Ⅱ对大鼠心室重构影响的实验研究[J].中国临床解剖学杂志,2007,25(6)：669-673.
[9]Zhan CD. The role of nitricoxide in the prevention of myocardial hypertrophicresponse and its mechanisms [J]. Sheng Li Ke Xue Jin Zhan,2000,31(4):322-324.
[10]钟南田,符史干,符皎荣,等.一氧化氮在压力超负荷心肌肥大作用中的定量分析[J].解剖学杂志,2005,28(5)：517-519.
[11]李永胜.丹参酮ⅡA对腹主动脉缩窄高血压大鼠心肌肥厚的作用及分子生物学机制[D].华中科技大学,2007.
[12]苟怀宇,陈艳秋,黄晶,等.银杏叶提取物对异丙肾上腺素诱导的大鼠 心肌肥厚的影响.重庆医科大学学报,2010,35(2)：224-226.
[13]王超,田岳凤,周丹,等.电针“内关”穴对心肌缺血再灌注大鼠心肌组织一氧化氮、一氧化氮合酶和细胞内钙的影响[J].针刺研究,2010,35(2)：113-117.
[1]Shiota N, Rysa J. A role for cardiac mast cells in the pathogenesis of hypertensive heart disease[J]. Hypertens,2003,21(10):1935-1944
[2]Isoda K, Kamezawa Y, Tada N, et al. Myocardial hypertrophy in tran-sgenic mice overexpressing human interleukin-la[J]. Journal of Cardiac Failure,2001,3 (4):355-364.
[3]张雪娟,徐庆科,谭凯,等.阿托伐他汀防止压力负荷导致心肌肥厚的抗炎机制[J].中华高血压杂志,2008,16(11)：1028-1032.
[4]Woldback PR,sande JB,stromme TA.Daily administration of interleukin-18 cause mycardial dysfunetion inhealthy mice [J]. Am J Physiol Heart Circ Physiol,2005,289:708-714.
[5]Takeda K, Ichiki T, Narabayashi E, etal. Inhibition of Prolyl Hydr-oxylase domain-containing pretein suppressed lipopolysaccha-ride induced TNF-a expression [J]. Arterioscler Thromb Vase Biol,2009,29 (12):2132-2137.
[6]Lin J,Liliensiek B, Kanitz M, et al.Molecular cloning of genes differentially regulated by TNF-alpha in bovine aortic endothelial cells, fibroblasts and smooth muscle cells [J]. Cardiovasc Res,1998 38(3):802-813.
[7]Janczewski AM, Kadokami T, Lemster B, et al. Morphological and fun-ctional changes in cardiac myocytes isolated from mice overexpre-ssing TNF-alpha[J]. Am J Physiol Heart Circ Physiol,2003,284 (3): H960.
[8]Kuwahara F, Kai H, Tokuda K, et al. Roles of Intercel lular Adhesion Molecule-1 in Hypertensive Cardiac Remodeling[J]. Hypertension, 2003,41:819-823.
[9]Shioi T, Matsumor i A, Kihara Y, et al. Increased expression of int-erleukin-1β and monocyte chemotactic and activating factor Pmonocyte chemoattractant Protein-1 in the hypertrophied and failing heart with Pressure overload [J]. Circ Res,1997,81(5): 664-671.
[10]Harada E, Nakagawa 0, Yoshimura M, et al. Effect of interleukin-1 β on cardiac hypertrophy and production of natriuretic pep tides in rat cardiocyte culture [J]. Mol Cell Cardiol,1999,31 (11):1997-2006.
[1]FreyN,Olson E N.Cardiac hypertrophy:the good, the bad and the ugly[J]. Annu RevPhysiol,2003,65:45-79.
[2]李向东,覃数.p38 MAPK在心肌肥厚中的作用机制[J].重庆医学,2007,36(14)：1438-1440.
[3]马文静,黄水清.p38丝裂原活化蛋白激酶在心血管疾病中的作用[J].中西医结合心脑血管病杂志,2008,6(7)：823-824.
[4]Dony JS, Han JH. Cellular activation mechanisms in septic shock [J]. Frontiers in Bioscience,1998,30 (3):468-476.
[5]Kyriakis JM, Avruch J.Protein kinase cascades activated by str-ess and inflammatory cytokinesstress [J].Bioes says,1996,18 (7): 567-577.
[6]GumRJ,MeLaughlinMM, KumarS, etal. Acquisition of sensitivity of stress-activated Protein kinases to the P38 in hibitor, SB203580, by alter ation of one or more aminoaeids with in the ATP binding Poeket[J].J Biol Chem,1998,273 (25):15605-15610.
[7]Lisnock J,Tebben A, Frantz B, et al. Molecular basis for p38-protein kinase inhibitor specificity [J]. Biochemistry,1998,37 (47): 16573-16581.
[8]肖翔林,谭莹,陈文瑛,等.p38促丝裂原活化蛋白激酶对疾病调控作用的研究进展[J].中国药房,2007,18(8)：622-624.
[9]杜俊英,方剑乔,梁宜,等.p38MAPK通路参与炎性痛及电针干预的可能性[J].医学信息,2011,24(6)：3612-3613.
[10]万顺伦,孙锦平,李召峰.应激后大鼠下丘脑磷酸化P38MapK的变化及电针足三里穴的调节作用[J].中华物理医学与康复杂志,2005,27(4)：202-204.
[11]龚伟,王升旭.电针夹脊穴在佐剂性关节炎大鼠镇痛过程中磷酸化p38丝裂原活化蛋白激酶的变化及作用[J].中国临床康复,2004,8(8)：1514-1515.
[12]王航,黄浩,蔡克银.电针夹脊穴通过磷酸化p38 MAPK信号通路对大鼠炎性痛阈的影响[J].安徽中医学院学报,29(5)：34-37.
[1]戴文建,王以光.心肌肥厚分子机制研究进展[J].心血管病学进展,2009,30(1)： 47-51.
[2]Nakagami H, Takemoto M, Liao JK. NADPH oxidase-derived superoxide anion mediates angiotensin Ⅱ-induced cardiac hypertrophy [J].J Mol Cell Cardio,2003,35 (7):851-859.
[3]Johnson JA. An epsilon PKC-selective inhibitor attenuates back phosphorylation of a low molecular weight protein in cardiac myoc-ytes[J].Cell Signal,2003,15 (1):123-130.
[4]FreyN, Olson E N.Cardiac hypertrophy:the good, the bad and the ugly[J]. Annu RevPhysiol,2003,65:45-79.
[5]Sugden P H. Signalling pathways in cardiac myocyte hypertrophy [J]. Ann Med.2001,33 (9):611-622.
[6]Kaiser R A, Liang Q R, Bueno 0 F, et al. Genetic inhibition or acti-vation of JNK1/2 protects the myoccadium from ischemia reperfus-ion-induced cell death in vivo [J]. J Biol Chem,2005,280(38):32602-32608.
[7]Han J, Lee JD, Tobias PS,et al.Endotoxin induces rapid proteint-yrosine phosphorylation in 70Z/3 cells expressing CD14[J]. JBiol Chem,1993,268(33):25009-25014.
[8]Toshiyuki O,Glenn EB, Michael BY. MAP kinase pathways activated by stress:The p38 MAPK pathway [J]·CritCare Med,2000,28 (4):N67-N77.
[9]Tyler Zarubin, Han JH.Activation and signaling of the p38 MAP kinase pathway [J]. Cell Res,2005,15 (1):11-18.
[10]魏倩萍,邓华聪,赵劫.p38MAPK信号通路在大鼠肾小球系膜细胞表达VEGF中的作用[J].重庆医学,2005,34(1)：16-18.
[11]Schafer PH,Wsdsworth SA, Wang. L-p38mitogen-activated protein kinase is activated CD28-mediated signaling and is required for IL-4production by hum_an CD4+T cells and effector cells [J].J Immunol,1999,162 (12):7110-7119.
[12]Gum RJ, McLaughlin MM, Kumar S, etal. Acquisition of Sensitivity of Stress-activated Protein Kinases to the p38 Inhibitor, SB 203580, by Alteration of One or More Amino Acids within the ATP Binding Pocket [J].JBiol Chem.1998,273(25):15605-15610.
[13]Boyle DL, Jones TL, Hammaker D, etal. Regulation of peripheral inflammation byspinal p38 MAPkinase in rats [J]. Plos Med,2006,3 (9): e338.
[14]Fu H, Bylund J, Karlsson A, et al. The mechanism for activation of the neutrophilNADPH-oxidase by the peptides formyl-Met-Leu-Phe and Trp-Lys-Tyr-Met-Val-Metdiffers from that for interleukin-8 [J]. Immunology,2004,112 (2):201-210.
[15]Piao CS,Kim JB, Han PL, et al. Administration of the p38 MAPK inhibitorSB203580 affords brain protection with a wide the rapeutic window against focal ischemic insul [J]. Neurosci Res,2003,73 (4): 537-544.
[16]Goedert M, Cuenda A,Craxton M, et al.Activation of the novel stress-aetivated Protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6):comparison of its substrate specificity with that of other SAP kinases [J]. EMBOJ,1997,16:3563-3571.
[17]吴松,李佳,洪亚群,等.内关治疗心系疾病理论基础探析[J].辽宁中医杂志,2011,38(11)：2178-2179.
[18]刁利红,杨宗保,周国祥,等.电针内关穴为主治疗无症状心肌缺血疗效观察[J].中国针灸,2011,31(7)：591-594.
[19]刁利红,周国祥,陈燕,等.针刺内关穴为主对无症状心肌缺血患者 临床疗效以及血脂和血液流变学的影响[J].中华中医药学刊,2011,29(6)：1315-1317.
[20]李培润,王辉,高晶,等.针刺内关穴治疗低脉压综合征临床观察[J].中医杂志,2003,44(4)：262.
[21]唐波炎.针刺内关穴治疗快速性心律失常的即时疗效观察[D].广州中医药大学,2010.
[22]汪桐,泮群皖.内关-心脏短反射的实验研究[J].针刺研究,1991,(2)：115-119.
[23]陈树林,李育良. 内关、心俞与心脏相关的神经基础[J].中国针灸.1996；10(12)：33-35.
[24]夏冬冬,王湖冰,谷禾,等.内关穴形态学特征及其临床意义[J].中国针灸,2010,30(12)：1003-1006
[25]闫丽萍,汪榈.内关心脏短反射的双向效应及其联系途径的研究[J].上海针灸杂志,2000,19(3)：32-35
[26]Wang H,Zhang HH,Wu XP, etal.Effect of e lectroacupunc-ture at neiguan point on the content of beta-endorphin in medullary bulb of rabbits with acute myocardial ischemia [J]. Chinese Journal of Clinical Rehabilitation, 2004,21(8):4384-4385.
[27]李明磊,王华,陈泽斌.电针内关穴对AMI大鼠自主神经与中枢P物质、一氧化氮合酶的影响[J].中华中医药杂志,2007,22(8)：543-546.
[28]涂乾,王华,王亚文,等.下丘脑室旁核对电针内关穴抗急性心肌缺血损伤作用的影响[J].中医杂志,2006,47(9)：665-667.
[29]林亚平,易受乡,严洁,等.针刺内关对心肌缺血再灌注损伤家兔CGRP和PGE2的影响[J].中国中医药信息杂志,2003,10(8)：26-28.
[30]田岳凤,吴富东,乔海法,等.针刺手厥阴心包经穴对心肌缺血再灌注损伤肌钙蛋白T的影响[J].中国中西医结合急救杂志,2003,10(1)：3-5.
[31]王华,邓丽霞,吴绪平,等.电针“内关”对室性心动过速大鼠心率及血浆儿茶酚胺含量的影响[J].针刺研究,2009,34(3)：180-183.
[32]李万山,钟敏,杨进,等.电针“内关”穴预处理对缺血再灌注大鼠心肌阿片受体基因表达的影响[J].中国针灸,2011,31(5)：441-444.
[33]吴松,唐宏图,陈泽斌,等.“双固一通”针法对急性心肌缺血模型大鼠心肌组织过氧化物酶活性的影响[J],湖北中医杂志,2006,28(10)：3-5.
[34]严洁,杨孝芳,易受乡,等.电针“内关”对心肌缺血再灌注损伤大鼠心肌细胞膜钠泵活性及其基因表达的影响[J].针刺研究,2007,32(5)：296-300.
[35]林亚平,严洁,王超,等.电针内关对心肌缺血再灌注损伤大鼠cTnT及bax基因表达的影响[J].湖南中医学院学报,2006,26(2)：40-42.
[36]唐宏图,吴松,陈泽斌,等.“双固一通”针法对老年实验性急性心肌缺血模型大鼠Mg2+ATPase的影响[J].上海针灸杂志2006；(7)：45-48.
[37]陈泽斌,唐宏图,吴松,等.“双固一通”针法对心肌缺血模型大鼠心肌组织Ca2+-ATPase活性的影响[J].湖北中医杂志2005；27(9)：15-16.
[38]王超,田岳凤,周丹.电针“内关”穴对心肌缺血再灌注大鼠心肌组织一氧化氮、一氧化氮合酶和细胞内钙的影响[J].针刺研究,2010,35(2)：113-117.
[39]姚凤祯,王岩.针刺家兔内关穴对快速型心律失常模型心肌细胞离子通道影响的研究[J].中医药信息,2010,27(5)：90-93.
[40]黄日龙,张伟,东贵荣.电针内关穴对急性心肌缺血家兔心肌组织能量代谢的实验研究[J].针灸临床杂志,2010,26(12)：44-48.
[41]张雪莲.电针“内关”穴对失血性低血压大鼠心肌cAMP-PKA细胞信号转导通路的影响[D].辽宁中医药大学,2009.
[42]苏全德.电针内关、郄门对冠心病患者心电图效应的对比观察[D].山东中医药大学,2007.
[43]蔡荣林,胡玲,汪克明,等.电针“内关”“太冲”穴对急性心肌缺 血家兔心功能的影响[J].针刺研究,2010,35(2)：104-108.
[44]金鸿韵.针刺多经经穴对健康人胃、小肠、心电影响的差异分析[D].湖北中医药大学,2011.
[45]胡玲,蔡荣林,吴子建,等电针不同经穴对急性心肌缺血家兔心功能的影响[J].针刺研究,2008,33(2)：88-93.
[46]王超,田岳凤,周丹.电针“内关”穴对心肌缺血再灌注大鼠心肌组织一氧化氮、一氧化氮合酶和细胞内钙的影响[J].针刺研究,2010,35(2)：113-117.
[47]李峰,冯耀光.大鼠心肌肥厚模型概述[J].中国现代医生,2011,48(32)：6-11
[48]王月兰,姚尚龙.丝裂原蛋白激酶信号转导通路在机械通气相关性肺损伤中的作用[J].中华实验外科杂志,2006,23(3)：331-333.
[49]鲁伟,刘培庆,王庭槐,等.MAPK信号途径在一氧化氮抑制大鼠心肌肥大中的作用.生理学报,2001,53(1)：32-36.
[50]Fi jen JW, Zi jlstra JG, De Boer P, et al. Suppression of the clinic-al and cytokineresponse to endotoxin by RWJ-67657,a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers [J] Clin Exp Immunol.2001,124(1):16-20.
[51]Liu H,Nishitoh H, Ichijo H, et al. Activation of apoptosis signal-regulating kinasel (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin[J]. Mol Cell Biol,2000,20 (6):2198-2208.
[52]Chen CC,Sun YT, ChenJJ,etal. Tumor necrosis factor-α-induced cyclooxygenase-2 expression via sequential activation of ceramide-dependent mitogenactivated protein kinase, and IkB kinase 1/2 in human alveolar epithelial cells [J]. Molpharmacol,2001,59 (3):493-500.
[53]McDermott E P,0 Neill L A.Ras participates in the activation of p38 MAPK byinterleukin-1 by associating with IRAK, IRAK2, TRAF6 and TAK-1[J].J Biol Chem,2002,277 (10):7808-7815.
[54]Perregaux DG, Dean D, Cronan M, et al. Inhibition of interleukin-1 beta production bySKF86002:evidence of two sites of in vitro activity and of a time and systemdependence [J]. Mol Pharmacol,1995, 48:433-442.
[1]Hughes SE.The pathology of hypertrophic cardiomyopathy [J]. Histopathology,2004,44 (5):412-427.
[2]Hirotani S, Otsu K, Nishida K, et al. Involvement of nuclear factor kappaB and apoptosis signal-regulating kinasel in G-protein coup-led receptor agonist-induced cardiomyocyte ertrophy[J]. Circula-tion,2002,105 (4):509-515.
[3]Han J, Lee JD, Tobias PS, et al. Endotoxin induces rapid proteint-yrosine phosphorylation in 70Z/3 cells expressing CD14[J]. Jbiol Chem,1993,268 (33):25009-25014.
[4]孙红霞.依那普利抗心肌纤维化作用及分子机制研究[D].吉林大学,2008.
[5]Toshiyuki 0, Glenn EB, Michael BY. MAP Kinase pathwaysactivated by stress:the p38MAPK pathway [J]. CritCare Med,2000,28 (4):67-77.
[6]Tyler Zarubin, Han JH. Activation and signaling of the p38 MAP kinase pathway [J]. Cell Res,2005,15 (1):11-18.
[7]Raingeaud J, Whitmarsh AJ, Barrett T, etal.MKK3 and MKK6 regulat-ed gene expression is mediated by the p38 mitogen activatedprote in kinase signal transduction pathway [J]. Mol Cell Biol,1996,16 (3): 1247-1255.
[8]Schafer PH, Wsdsworth SA, Wang L. p38a mi togen-act ivated prote-in kinase is activated CD28-mediated signaling and is required for IL-4 product ion by human CD4+ Tcells and effector cells [J]. J Immu-nol,1999,162 (12):7110-7119.
[9]GumRJ,MeLaughlinMM, KumarS, etal. A equisition of sensitivity of stress-activated Protein kinases to the P38 inhibitor, SB203580, by alter ation of one or more aminoaeids with in the ATP binding Poeket[J]. JB101 Chem,1998,273 (25):15605-15610.
[10]Boyle DL,Jones TL, Hammaker D, et al. Regulation of peripheral inflammation byspinal p38 MAPkinase in rats [J]. PloS Med,2006,3(9): e338.
[11]Fu H, Bylund J,Karlsson A, et al.The mechanism for activation of the neutrophilNADPH-oxidase by the peptides formyl-Met-Leu-Phe and Trp-Lys-Tyr-Met-Val-Metdiffers from that for interleukin-8 [J]. Immunology,2004,112 (2):201-210.
[12]Piao CS,Kim JB, Han PL, et al. Administration of the p38 MAPK inhibitorSB203580 affords brain protection with a wide the rapeutic window against focal ischemic insul [J]. Neurosci Res,2003,73 (4): 537-544.
[13]Goedert M, Cuenda A, Craxton M, et al. Activation of the novel stress-aetivated Protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6):comparison of its substrate specificity with that of other SAP kinases[J]. EMBOJ,1997,16: 3563-3571.
[14]Ritchie RH,Delbridge LMD. Cardiac hypertrophy, substrate uti-lization and metabolic remodelling:cause or effect[J]. Clin Exp Pharmacol Physiol,2006,33 (1-2):159-166
[15]Tsujimoto I, Hikoso S, Yamaguchi 0, et al. The antioxidant edara-vone attenuates pressure overload-induced leftventricular hyper-trophy [J]. Hypertension,2005,45 (5):921-926.
[16]Cheng TH, Shih NL, Chen CH, et al.Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chaingene expression and cardiomyocyte hypertrophy [J]. J Biomed Sci,2005,12 (1):123-133.
[17]Braz JC, Bueno OF, Liang Q, et al. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathythrough upregulation of calcineurin-NFAT signaling [J]. JClin Invest,2003,111 (10):1475-148 6.
[18]Pu L,Dimitrios G, Attila K. The in vivo role of p38MAPkinases in cardiac remodeling and restrictive cardiomyopa-thy [J]. Proc Natl Acad Sci USA,2001,98 (21):12283-12288.
[19]See F, Thomas W, Way K, et al. p38 mitogen-activatedprotein kin-ase inhibition improves cardiac function and at-tenuates left ventricular remodeling following myocardialinfarction in the rat[J].J Am Coll Cardiol,2004,44 (8):1679-1689.
[20]Matsumoto M, Takimoto Y, Aoyama T, et al. Activation of TGF-betal-TAK1-p38 MAPK pathway in spared cardiomyocytes isinvolved in left ventricular remodeling after myocardial infarction in rats [J].Am J Physiol Heart Circ Physiol,2006,290 (2):709-715.
[21]Zhang D,Gaussin V,Taffet GE, et al. TAK1 is activatedin the myocardium after pressure overload and is suffi-cient to provoke heart failure in transgenic mice[J].Nat Med,2000,6 (5):556-563.
[22]李向东,覃数.p38 MAPK在心肌肥厚中的作用机制[J].重庆医学,2007,36(14)：1438-1440.
[1]张云飞,吴先均,文秀华,等.心肌肥厚机制研究进展[J].心血管病学进展,2005,26(2)：197-200.
[2]陈修,陈维洲,曾贵云.心血管药理学[M](第三版).人民卫生出版社,2002.
[3]张明国,李雪峰.细胞调亡在心血管病中的研究[J].医学综述,2004,10(8)：470-472.
[4]Motoaki Sano,Keiichi Fukuda,Toshiniko Sato. ERK and p38MAPK, but not NF-KB, are criticallly involved in reactive oxygen species-mediated induction of IL-6 by angiotensinⅡ in cardiac fibroblasts [J]. CircRes,2001,89 (8):661-669.
[5]Henry E Kim, Seema S Dalal, Erik Young. Disruption of the myocardi-al extracellular matrix leads to cardiac dysfunction[J]. J Clin Invest,2000,106 (7):857-866.
[6]Aoki H, RichmondM, Izumo S et al. Specific role of the extracel lu-lar-signal-regulated kinase pathway in Angiotensin Ⅱ-in-duced cardiac hypertrophy in vitro [J]. Biochem J,2000,347(1):275-284.
[7]George W Booz, Jonathan N E Day, Kenneth M Baker. Interplay between the cardiac rennin angiotensin system and JAK-STAT signaling:role in cardiac hypertrophy, ischemia/repefusion dysfunction, and heart failure[J].J Mol Cell Cardiol,2002,34 (11):1443-1453.
[8]殷仁富,陈金明.心脏能量学[M].第二军医大学出版社,2002.
[9]Wang X, Dhalla NS. Modification of beta-adrenoceptor signal tra-nsduction pathway by geneticmanipulation and heart failure [J]. Mol Cell Biochem,2000,214(1-2):131-15.
[10]金惠铭,卢建,殷莲华.细胞分子病理生理学[M].郑州大学出版社,2002.
[11]Zhao XS, Pan WT, Raffi B, etal. Endogenous endothel in-1 is requir-ed forcardiomyocyte survival in vivo[J]. Circulation,2006,114: 830-837.
[12]油红文,陈曦,油红捷,等.内皮素及其受体对心脏细胞肥大与增殖的作用[J].中国医学科学院学报,2006；28(4)：520-523.
[13]Nobutake S, Subrina J, SohelZ, etal. Eicosapentaenoic acid prev-ents endothelin-1-induced cardiomyocyte hypertrophy in vitro through the suppression of TGF-β1 and phosphorylated JNK [J]. Am J Physiol Heart Circ Physiol 2006,291 (2):H835-H845.
[14]Zhu W, Zou Y, Shio j ima I, et al. Ca2+/calmodul in-dependent kinase II and calcineurin play critical roles in endothelin-1-induced cardiomyocyte hypertrophy [J]. J Biol Chem,2000,275 (20):15239-1524 5.
[15]Tanaka K,Honda M, Takabatake T. Redox regulation of MAPK path-ways and cardiac hypertrophy in adult rat cardiac myocyte[J].J Am Coll Cardiol,2001,37 (2):676-685.
[16]Wang YZ,Luo JD,Liu XH.Simvastain inhibits ROS mediated the neonatal rat cardiacmyocyte hypertrophy induced by endothelin-1 [Jl.Chin Pharmacol Bull,2003,19 (8):871-875.
[17]Zhan CD. The role of nitricoxide in the prevention of myocardial hypertrophicresponse and its mechanisms[J]. Sheng Li Ke Xue Jin Zhan,2000,31(4):322-324.
[18]Harada E, Yoshimura M, Yasue H, et al. Aldostrone induces angiote-nsin converting-enzyme gene expression in cultured neonatal ratcardiocytes [J]. Circulation,2001,104 (2):137-139.
[19]Takeda Y, Yoneda T, Demura M, et al. Calcineurin inhibition atten-uates mineralocorticoid-induced cardiac hypertrophy[J]. Circulat-ion,2002,105 (6):677-679.
[20]李凌峰,陈良万.心肌肥厚发生机制研究[J].海南医学,2008,19(7)：123-125.
[21]Knowles JW, Esposito G, Mao L, etal. Pressure-independent enhan-cement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice[J].J Clin Invest,2001,107 (8):975-984.
[22]刘洪梅,刘彤,黄体钢.高血压左室肥厚兔心房利钠肽水平和左房直径的变化[J].陕西医学杂志,2008,37(4)：405-407.
[23]马晓庆,苏胜偶.内皮素、血管紧张素Ⅱ、转化生长因子β1与心肌肥厚关系的研究进展[J].中国老年学杂志,2009,29(6)：766-768.
[24]BaudinoTA, CarverW, GilesW, et al. Cardiac fibroblasts:friend or foe [J]. Am J PhysiolHeartCirc Physiol,2006,291 (3):1015-1026.
[25]谢亚芹,周青云,康大伟.TGF-β1与慢性心力衰竭大鼠心肌肥厚的关系[J].中国老年学杂志,2011,31(7)：1183-1187.
[26]李永胜,严丽,雍永权.丹参酮ⅡA对高血压大鼠肥厚心肌TGF-β 1/Smads信号通路的影响[J].中国中西医结合杂志,2010,30(5)：499-504.
[27]Rosenkranz S, FleschM, Bohm M, et al. Alterations of beta-adrene-rgic signaling and cardiac hypertrophy in transgenicmice overexpr-essing TGF-beta(1) [J]. Am J Physiol Heart Circ Physiol,2002,283 (3): 1253-1262.
[28]罗惠兰,何作云,冯兵,等.人心肌肥大时碱性成纤维细胞生长因子和转化生长因子表达的变化及其意义[J].中华心血管病杂志,2001,29(7)：402-406.
[29]Cittadini A, Stromer H, Katz SE, et al. Differential cardiac effe-cts ofgrowth hormone and insulin-like growth factor-1 in the rat:a combined in vivo and in vitro evaluation [J]. Circulation,1996,93 (4):800-809.
[30]黄顺伟,唐可京,高修仁.原发性高血压合并心肌肥厚与胰岛素样生长因子-1的关系研究[J].中国循环杂志,2004,19(3)：202-204.
[31]Weismuller T, KLEIN J, Loffelholz K. Effects of norepinephrine and cardiotrophin-1 on phospholi-pase dactivity and incorporation of myristic acidinto phosphatidylcholine in rat heart [J]. J Pharma-co Sci,2004,95 (3):335-340.
[32]Jougasaki M, Tachibana I, Luchner A, et al. Augmented cardiac cardiotrophin-1 in experimental congestive heart failure [J].Cir culation,2000,101(1):14-17.
[33]Shioi T,Matsumori AKihara Y, et al. Increased expression of interleukin-1 β and monocyte chemotactic and activating factor Pmonocyte chemoattractant Protein-1 in the hypertrophied and failing heart with Pressure overload [J]. Circ Res,1997,81(5): 664-671.
[34]Harada E, Nakagawa O, Yoshimura M, et al. Effect of interleukin-1 (3 on cardiac hypertrophy and production of natriuretic peptides in rat cardiocyte culture [J]. Mol Cell Cardiol,1999,31 (11):1997-2006.
[35]Janczewski AM,Kadokami T,Lemster B,et al.Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alPha[J]. Am J Physiol Heart Circ Physiol,2003, 284 (3):H960.
[36]Liu H, Ni shit oh H, Ichi jo H, et al. Activation of apoptosis signal regulating kinasel (ASK1) by tumor necrosis factor receptor associa-ted factor2 requires prior dissociationof the ASK1 inhibitor thioredoxin[J].MolCell Biol,2000,20 (6):2198-2208.
[37]Chen CC,Sun YT,ChenJJ,et al. Tumor necrosis factor a induced cyclooxygenase-2 expression via sequential activation of ceramide-dependent mitogenactivated protein kinase, and IkB kinase1/2 in human alveolar epithelial cells [J]. Molpharmacol,2001,59(3):493-500.
[38]Me Dermott EP,O Neill LA. Ras participates in the activation of p38 MAPK byinterleukin-1 by associating with IRAK, IRAK2, TRAF6 and TAK-1[J].J Biol Chem,2002,277 (10):7808-7815.
[39]黄政德,李鑫辉,谢雪姣,等.活血化瘀药对血瘀证心肌缺血再灌注损伤家兔内源性活性因子及炎症因子的影响[J].中华中医药学刊,2007,25(7)： 1319-1321.
[40]戴文建,王以光.心肌肥厚分子机制研究进展….心血管病学进展,2009,30(1)：47-51.
[41]Nakagami H, Takemoto M, Liao JK. NADPH oxidase-derived superox-ide an ion mediates angiotensin Ⅱ-induced cardiac hypertrophy [J]. J Mol Cell Cardio,2003,35(7):851-859.
[42]Johnson JA. An PKC-selective inhibitor attenuates back phosph-orylation of a low molecular weight protein in cardiac myocytes [J].Cell Signal,2003,15:123-130.
[43]Frey N, Olson EN. Cardiac hypertrophy:the good, the bad and the ugly[J]. Annu RevPhysiol,2003,65:45-79.
[44]Sugden P H. Signalling pathways in cardiac myocyte hypertrophy [J]. Ann Med.2001,33 (9):611-622.
[45]Kaiser RA, Liang QR, Bueno OF, et al. Genetic inhibition or activ-ation of JNK1/2 protects the myoccadium from ischemia reperfusion-induced cell death in vivo[J]. J Biol Chem,2005,280 (38):32602-3260 8.
[46]Manning G, Whyte DB,Martinez R, et al. The protein kinase comple-ment of the human genome [J]. Science,2002,298 (5600):1912-1934.
[47]Widmann C, Gibson S, Jarpe MB, et al. Mitogen-activated protein kinase:congservation of a three-kinase module from yeast to human[J]. Physiol Rev1999,79 (1):143-180.
[48]Tori is, Nakayama K, Yamamoto T, et al. Regulatory mechanisms function of ERK MAP kinases[J].J Riochem,2004,136 (5):557-561.
[49]Sebolt-Leopold JS,Herrera R.Targeting the mitogen-activated protein kinase cascade to treat cancer[J]. Nat Rev Cancer,2004,4 (12):937-947.
[50]Haq S, Choukroun G,Lim H, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure [J]. Circulation.2001,103 (5):670-677.
[51]Wang L, Proud CG. Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes [J].Circ. Res.2002,91 (9):821-829.
[52]王祥,戴友平,杨杪,等.心房颤动心房组织内细胞外信号调节激酶和血管紧张素转化酶表达的研究[J].中华心血管病杂志,2004,32(3)：207-210.
[53]Davis RJ.Signal transduction by the JNK group of MAPkinases [J]. Cell,2000,103 (2):239-252.
[54]Sugden PH. Signalling pathways in cardiac myocyte hypertrophy [J].Ann Med 2001; 33 (9):611-622.
[55]Frazier D P, Wilson A, Dongherty C J, et al. PKC-alpha and TAK-1 are interm ediates in the activation of c—Jun NH2. terminal kinase by hypoxia—reoxygenation[J]. Am J Physiol Heart Circ Physiol,2007, 292 (4):1675-1684.
[56]Kaiser RA, Liang QR, Bueno OF, et al. Genetic inhibition or acti-vation of JNK1/2 protects the myoccadium from ischemia reperfusion-induced cell death in vivo [J]. J Biol Chem,2005,280(38):32602-3 2608.
[57]Martindale JL, Holbrook NJ. Cellular response to oxidative stress:signaling for suicide and survival [J]. J Cell Physiol,2002, 192(1):1-15.
[58]Nemoto S, Sheng Z, Lin A. Opposing effects of Jun kinase and P38 mitogen activated protein kinases on caridomyocyte hypertrophy [J].Mol Cell Biol,1998,18 (6):3518-3126.
[59]Toshiyuki 0, Glenn EB, Michael BY. MAP Kinase pathwaysactivated by stress:the p38MAPK pathway [J]. CritCare Med,2000,28 (4):67-77.
[60]Tyler Zarubin, Han JH. Activation and signaling of the p38 MAP kinase pathway [J]. Cell Res,2005,15 (1):11-18.
[61]魏倩萍,邓华聪,赵劫.p38MAPK信号通路在大鼠肾小球系膜细胞表达VEGF中的作用[J].重庆医学,2005,34(1)：16-18.
[62]Vallentin A,Mochly-Rosen D.RBCK1,a protein kinase Cbetal (PKCbetaI)-interacting protein, regulates PKC beta-dependent func-tion [J].J Biol Chem,2007,282 (3):1650-1657.
[63]刘丽娜,李法琦.心肌肥厚相关信号通路的研究进展[J].重庆医学2010,39(20)：2805-2808.
[64]王曙霞,惠汝太.心肌肥厚信号传导通路的研究进展[J].中国分子心脏病学杂志,2006,6(6)：363—368.
[65]WANG PY, LIU J,XU SM, et al. Nuclear Ca2+ transport of isoprenali-ne induced heart hypertrophy in rats[J]. Chinese Journal of pharmacology and Toxicology,2002,16 (1):25-30.
[66]谭建新,陈新民,王优,等.钙调神经磷酸酶信号通路介导大鼠慢性缺氧性右心室心肌肥厚[J].实用儿科临床杂志,2008,23(13)：1002-1004.
[67]Muth JN. Bodi I. Lewis W, et al. A Ca2+-dependent transgenic model of cardiachypertrophy:A role for protein kinase Calpha[J]. Circulation.2001,103(1):140-147.
[68]Morisco C,Zebrowski D,Condorelli B, et al.The Akt-glycogen synthase kinase3beta pathway regulates transcription of arrial natriuretic factor induced bybeta-adrenergic receptor stimulation in cardiac myocytes [J]. J Biol Chem,2000,275 (19):14466-14475.
[69]Shiojima I,Walsh K.Regulation ofcardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway [J]. GenesDev,2006,20 (24):3347-3365.
[70]Condorelli G, Drusco A, Stassi G, et al.Akt induces enhanced myocardial contractility and cell size in vivo in transgenicmice [J].Proc Natl Acad Sci USA,2002,99 (19):12333-12338.
[71]穆灵敏,王文锋,郭志坤,等.PI3K Akt蛋白在异丙肾上腺素所致大鼠心肌肥厚中的表达[J].四川动物,2010,29(4)：560-563.
[72]Kunisada K, Negoro S, Tone E, et al. Signal transducer and activa-tor of transcription3 in the heart transduces not only a hypertroph-ic signal but a protective signal against doxorubicin-induced cardiomyopathy[J].Natl Acad Sci USA,2000,97 (1):315-319.