The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice
The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice
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DOI：
10.1152/ajpregu.00424.2007
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发表时间：
2008-01-01
影响因子：
2.8
通讯作者：
Brum, P. C.
中科院分区：
文献类型：
--
作者：
Ferreira, J. C. B.;Bacurau, A. V.;Brum, P. C.
交感神经功能亢进（SH）和肾素血管紧张素系统（RAS）激活通常与心力衰竭（HF）相关，尽管这些因素对心脏紊乱的相对贡献尚不清楚。在缺乏α（2A）和α（2C）肾上腺素受体敲除（α（2A）/α（2C）ARKO）的小鼠中研究了SH对RAS组分的作用及其对HF的影响，这些小鼠在7月龄时呈现SH并有HF的证据。在3月龄和7月龄的雄性成年小鼠中评价心脏和全身RAS组分和血浆去甲肾上腺素（PN）水平。此外，还进行了心脏形态学分析、胶原含量、运动耐量和血流动力学评估。在3个月时，与野生型小鼠（WT）相比，α（2A）/α（2C）ARKO小鼠未显示HF体征，同时显示PN升高、局部和全身RAS组分激活以及心肌细胞宽度增加（16%）。相比之下，在7个月时，α（2A）/α（2C）ARKO小鼠表现出明显的HF体征，仅伴有血管紧张素原和ANG II水平的心脏激活和胶原蛋白含量增加（两倍）。与RAS的这种局部激活一致，8周的ANG II AT（1）受体阻滞剂治疗恢复了与WT相当的心脏结构和功能。总的来说，这些数据提供了直接的证据，心脏RAS激活起着重要的作用，潜在的结构和功能异常与遗传SH诱导的HF小鼠。
Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking alpha(2A) and alpha(2C) adrenoceptor knockout (alpha(2A)/alpha(2C) ARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, alpha(2A)/alpha(2C)ARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, alpha(2A)/alpha(2C)ARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT(1) receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.