Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice
Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice
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DOI：
10.1172/jci35620
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发表时间：
2009-02-01
影响因子：
15.9
通讯作者：
Kass, David A.
中科院分区：
文献类型：
--
作者：
Takimoto, Eiki;Koitabashi, Norimichi;Kass, David A.
心脏最初通过增强其收缩力和发展肥大而不扩张来补偿高血压介导的压力超负荷。G（q）蛋白偶联受体通路被激活，并可抑制功能，导致心力衰竭。在这种刺激过程中减少心脏损伤的初始适应机制在很大程度上仍然未知。在这里，我们已经表明，这种最初的适应需要调节G蛋白信号2（RGS 2）。缺乏RGS 2的小鼠具有正常的基础心脏表型，但对压力超负荷反应迅速，心肌G。信号传导、显著的心脏肥大和衰竭以及早期死亡率。不伴随Gq激活的游泳运动诱导了正常的心脏反应，而在G（α q）过表达的心脏中Rgs 2缺失则加剧了肥大和扩张。在血管平滑肌中，RGS 2被cGMP依赖性蛋白激酶（PKG）激活，抑制G（q）刺激的血管收缩。在正常小鼠中，但不是Rgs 2（-/-）小鼠，PKG激活cGMP选择性磷酸二酯酶S（PDES）的慢性抑制抑制适应不良的心脏肥大，抑制G（q）耦合刺激。重要的是，PKG在心肌中通过PDES抑制被类似地激活。从两种基因型，但PKG质膜易位是更短暂的Rgs 2（-/-）心肌细胞比对照组，并不受PDES抑制。因此，RGS 2是压力超负荷的早期心肌补偿所必需的，并介导RDE 5抑制剂的初始抗肥大和心脏保护作用。
The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. G(q) protein-coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial G. signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by Gq activation, induced a normal cardiac response, while Rgs2 deletion in G(alpha q)-overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing G(q)-stimulated vascular contraction. In normal mice, but not Rgs2(-/-) mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase S (PDES) suppressed maladaptive cardiac hypertrophy, inhibiting G(q)-coupled stimuli. Importantly, PKG was similarly activated by PDES inhibition in myocardium. from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2(-/-) myocytes than in controls and was unaffected by PDES inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of RDE5 inhibitors.