Angiotensin II type-1 receptor activation in the adult heart causes blood pressure-independent hypertrophy and cardiac dysfunction
Angiotensin II type-1 receptor activation in the adult heart causes blood pressure-independent hypertrophy and cardiac dysfunction
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DOI：
10.1093/cvr/cvn230
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发表时间：
2009-02-15
影响因子：
10.8
通讯作者：
Ball, Stephen G.
中科院分区：
文献类型：
--
作者：
Ainscough, Justin F. X.;Drinkhill, Mark J.;Ball, Stephen G.
持续的高血压导致心脏肥大，其可通过病理重构进展为心力衰竭。肾素-血管紧张素系统（RAS）的异常与此过程密切相关。虽然在人类的肥大是一个既定的风险因素独立于血压（BP），分离的重塑反应的局部线索内分化的心肌与压力超负荷相关的尚未解决。本研究旨在阐明局部RAS活性的作用，特别是在成年心脏，在调节心脏肥大和病理modeling.Transgenic小鼠诱导心肌细胞特异性表达的野生型或N111 G突变形式的人血管紧张素II（Ang II）1型受体（hAT 1 R）。野生型受体主要由Ang II刺激。相比之下，N111 G受体也可以被Ang II衍生物Ang IV以不刺激野生型受体的水平完全刺激。这些模型的独特性质用于研究在正常条件下和在Ang IV输注后对hAT 1 R刺激的心肌生长、重构和功能反应，特别是在成年心肌细胞中。从青春期开始，在心肌细胞膜上低水平表达野生型或N111 G hAT 1 R，诱导成人心肌细胞生长增强和相关的心肌肥大。这与通过纵向遥测分析测量的静息BP或心率变化无关，并且没有进展为病理性重塑或心力衰竭。然而，选择性激活心肌细胞特异性N111 G受体的血管紧张素IV肽输注诱导不利的心室重构4周内。其特征是间质纤维化增加、左心室扩张和心功能受损。分化心肌中低水平的局部AT 1 R活性导致代偿性心脏肥大，即心肌质量增加但保留正常功能，而短期增加刺激诱导心功能障碍，伴随扩张、射血分数降低、以及在全身血压没有变化的情况下纤维化增加。
Sustained hypertension leads to cardiac hypertrophy that can progress, through pathological remodelling, to heart failure. Abnormality of the renin-angiotensin system (RAS) has been strongly implicated in this process. Although hypertrophy in human is an established risk factor independent of blood pressure (BP), separation of remodelling in response to local cues within the differentiated myocardium from that related to pressure overload is unresolved. This study aimed to clarify the role of local RAS activity, specifically in the adult heart, in modulating cardiac hypertrophy and pathological remodelling.Transgenic mice with inducible cardiomyocyte-specific expression of a wild-type or N111G mutant form of the human angiotensin II (Ang II) type-1 receptor (hAT1R) were generated. The wild-type receptor is primarily stimulated by Ang II. In contrast, the N111G receptor can also be fully stimulated by the Ang II derivative, Ang IV, at levels that do not stimulate the wild-type receptor. The unique properties of these models were used to investigate the myocardial growth, remodelling and functional responses to hAT1R stimulation, specifically in adult cardiomyocytes, under normal conditions and following Ang IV infusion. Low-level expression of wild-type or N111G hAT1R at the cardiomyocyte membrane, from the onset of adolescence, induced enhanced myocyte growth and associated cardiac hypertrophy in the adult. This was not associated with change in resting BP or heart rate, measured by longitudinal telemetric analysis, and did not progress to pathological remodelling or heart failure. However, selective activation of cardiomyocyte-specific N111G receptors by Ang IV peptide infusion induced adverse ventricular remodelling within 4 weeks. This was characterized by increased interstitial fibrosis, dilatation of the left ventricle, and impaired cardiac function.Low-level local AT1R activity in differentiated myocardium causes compensated cardiac hypertrophy, that is, increased myocardial mass but with the retention of normal function, whereas short-term increased stimulation induces cardiac dysfunction with dilatation, reduced ejection fraction, and increased fibrosis in the absence of change in systemic BP.