Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure
Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure
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DOI：
10.1161/01.hyp.0000173069.53699.d9
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发表时间：
2005-08-01
期刊：
影响因子：
8.3
通讯作者：
Delbridge, LMD
中科院分区：
文献类型：
--
作者：
Domenighetti, AA;Wang, Q;Delbridge, LMD
血浆血管紧张素II(Ang II)的慢性升高对心脏有害。除了血流动力学作用外，Ang II还具有心肌营养作用，有助于心肌细胞重塑。然而，在血流动力学没有改变的情况下，血管紧张素II的这些直接作用是否足以导致收缩功能障碍和心力衰竭仍有待阐明。在这项研究中，我们使用TG1306/1R(TG)小鼠在没有血压升高的情况下形成Ang II介导的心肌肥大，以研究心肌细胞在对慢性心脏特异性内源性Ang II刺激的适应性反应中的表型变化。一项为期94周的纵向研究表明，与野生型(WT)小鼠相比，TG小鼠随着年龄的增长而患上扩张型心肌病，并表现出显著的死亡率增加。TG小鼠心肌肥大与心肌细胞肥大(15~20周：长度+20%；35~40周：长度+10%，宽度+15%)相关，但与胶原沉积无关。体内心功能分析显示，TG小鼠存在年龄依赖性的收缩和舒张期功能障碍(与WT相比，50-60周龄的dp/dt(Max)和dp/dt(Min)大约减少45%)。对分离的心肌细胞等张缩短的分析显示，TG心肌细胞的收缩能力受损(缩短和延长率下降30%至40%)。在TG心脏中，慢性Ang II暴露导致肌浆网钙泵(SERCA2)下调和钙瞬变减少，表明潜在的钙稳态紊乱。总而言之，慢性Ang II心肌刺激在没有血流动力学超负荷的情况下足以产生心肌细胞和心功能障碍，最终导致心力衰竭。
Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II - mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy ( 15 to 20 weeks: length + 20%; 35 to 40 weeks: length + 10%, width + 15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice ( approximate to 45% reduction in dP/dt(max) and dP/dt(min) at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.