Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Nature. 2012 Aug 16;488(7411):394-8. doi: 10.1038/nature11263.
Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.
心肌肥厚最初是作为对持续超负荷的适应性反应而发生的，但随着心力衰竭的发生，它会病理性地进展。在这里，我们报告了 G 蛋白偶联受体 APJ 的遗传缺失赋予了对慢性压力超负荷的抗性，显著减少了心肌肥厚和心力衰竭。相比之下，缺乏内源性 APJ 配体 apelin 的小鼠仍然敏感，这表明 APJ 具有 apelin 独立的功能。新分离的 APJ 缺失心肌细胞对拉伸的反应减弱，表明 APJ 是一种机械感受器。拉伸激活 APJ 增加心肌细胞大小并诱导肥大的分子标志物。虽然 apelin 刺激 APJ 激活 Gαi 并引发保护反应，但拉伸信号以 APJ 依赖、G 蛋白独立的方式诱导肥大。通过β-arrestin 的敲低或通过作用于 Gαi 的药理学剂量的 apelin 来预防拉伸介导的肥大。综上所述，我们的数据表明 APJ 是机械拉伸和内源性肽 apelin 的双功能受体。通过感知这些刺激之间的平衡，APJ 占据了将持续超负荷与心肌细胞肥大联系起来的关键位置。
