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APJ acts as a dual receptor in cardiac hypertrophy

机译:APJ在心脏肥大中充当双重受体

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摘要

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 Gα_i 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 p-arrestins or by pharmacological doses of apelin acting through Gα_i. 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.
机译:心脏肥大是对持续性超负荷的一种适应性反应,但随着心力衰竭的发生,病理上会发展。在这里我们报告说,APJ(一种G蛋白偶联受体)的遗传损失通过显着减少心肌肥大和心力衰竭而赋予了对慢性压力超负荷的抵抗力。相反,缺乏apelin(内源性APJ配体)的小鼠仍然敏感,表明APJ具有apelin独立的功能。新鲜分离的无APJ的心肌细胞对牵张的反应减弱,这表明APJ是一种机械传感器。通过拉伸激活APJ会增加心肌细胞的大小,并诱导肥大的分子标记。而apelin刺激APJ激活Gα_i并引起保护性反应,而以APJ依赖性,G蛋白非依赖性的方式拉伸信号以诱导肥大。通过抑制p-arrestin或通过Gα_i作用的药理剂量的apelin可以预防拉伸介导的肥大。两者合计,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占据了一个关键点,将持续的超负荷与心肌肥大联系起来。

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  • 来源
    《Nature》 |2012年第7411期|p.394-398|共5页
  • 作者单位

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Department of Pediatrics, School of Medicine, Stanford University. California 94305, USA;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Department of Medicine, School of Medicine, Stanford University, California, 94305, USA;

    Department of Pharmacology, University of California, San Diego. California, USA;

    Biomedical and Genetic Research Institute, National Research Council, via Fantoli 16/15, 20138, Milan, Italy,Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Wyeth Pharmaceutical, Madison, New Jersey, USA;

    Wyeth Pharmaceutical, Madison, New Jersey, USA,Sirtris, a GSK Company, Cambridge, Massachusetts 02139, USA;

    Institute of Biomedical Research, August Pi i Sunyer (IDIBAPS), E-O8036 Barcelona, Spain;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Department of Medicine, School of Medicine, Stanford University, California, 94305, USA;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;

    Department of Pharmacology, University of California, San Diego. California, USA;

    Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA,Department of Pediatrics, School of Medicine, Stanford University. California 94305, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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