Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06510, USA.
J Clin Invest. 2013 Apr;123(4):1718-31. doi: 10.1172/JCI65112.
Myocardial hypertrophy is an adaptation to increased hemodynamic demands. An increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain and adequate supply of oxygen and nutrients for the heart. The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. We report that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism. We used transgenic, conditional overexpression of placental growth factor (PlGF) in murine cardiac tissues to stimulate myocardial angiogenesis and increase endothelial-derived NO release. NO production, in turn, induced myocardial hypertrophy by promoting proteasomal degradation of regulator of G protein signaling type 4 (RGS4), thus relieving the repression of the Gβγ/PI3Kγ/AKT/mTORC1 pathway that stimulates cardiomyocyte growth. This hypertrophic response was prevented by concomitant transgenic expression of RGS4 in cardiomyocytes. NOS inhibitor L-NAME also significantly attenuated RGS4 degradation, and reduced activation of AKT/mTORC1 signaling and induction of myocardial hypertrophy in PlGF transgenic mice, while conditional cardiac-specific PlGF expression in eNOS knockout mice did not induce myocardial hypertrophy. These findings describe a novel NO/RGS4/Gβγ/PI3Kγ/AKT mechanism that couples cardiac vessel growth with myocyte growth and heart size.
心肌肥厚是对增加的血液动力学需求的一种适应。心脏组织的增加必须与冠状动脉血管的相应扩张相匹配，以维持和提供心脏的氧气和营养物质的充足供应。协调血管生成和心肌细胞生长的生理机制尚不清楚。我们报告说，心肌血管生成的诱导通过一种新的 NO 依赖性机制促进心肌细胞生长和心脏肥大。我们使用胎盘生长因子（PlGF）在小鼠心脏组织中的转基因、条件过表达来刺激心肌血管生成并增加内皮衍生的 NO 释放。反过来，NO 产生通过促进 G 蛋白信号转导调节因子 4（RGS4）的蛋白酶体降解来诱导心肌肥大，从而解除抑制 Gβγ/PI3Kγ/AKT/mTORC1 通路的抑制作用，该通路刺激心肌细胞生长。在心肌细胞中同时过表达 RGS4 可防止这种肥大反应。NOS 抑制剂 L-NAME 也显著减少了 RGS4 的降解，并减少了 PlGF 转基因小鼠中 AKT/mTORC1 信号的激活和心肌肥大的诱导，而内皮型一氧化氮合酶（eNOS）敲除小鼠中的条件性心脏特异性 PlGF 表达并未诱导心肌肥大。这些发现描述了一种新的 NO/RGS4/Gβγ/PI3Kγ/AKT 机制，它将心脏血管生长与心肌细胞生长和心脏大小联系起来。
