Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice
Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice
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DOI：
10.1172/jc1200315598
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发表时间：
2003-02-01
影响因子：
15.9
通讯作者：
Blumer, KJ
中科院分区：
文献类型：
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作者：
Heximer, SP;Knutsen, RH;Blumer, KJ
激素和神经递质激活G蛋白偶联受体（GPCRs）的信号传导使血压保持在正常范围内，尽管心输出量可能在几秒钟内发生巨大变化。这意味着血压调节需要GPCR信号传导的精确动力学控制。为了验证这一假设，我们分析了RGS 2缺陷的小鼠，RGS 2是一种GTP酶激活蛋白，在体外大大加速了异源三聚体G蛋白的失活速率。rgs 2（+/-）和rgs 2（-/-）小鼠均表现出强烈的高血压表型、肾血管异常、阻力血管系统持续收缩以及体内血管系统对血管收缩剂的反应延长。体外血管平滑肌细胞中P2 Y受体介导的Ca 2+信号传导的分析表明，RGS 2的丧失增加了激动剂的效力和功效，并减缓了信号终止的动力学。这些结果表明，G蛋白偶联血管收缩受体异常延长的信号传导可能导致高血压的发生，并且他们表明影响RGS 2功能或表达的遗传缺陷可能是人类高血压发展的新风险因素。
Signaling by hormones and neurotransmitters that activate G protein-coupled receptors (GPCRs) maintains blood pressure within the normal range despite large changes in cardiac output that can occur within seconds. This implies that blood pressure regulation requires precise kinetic control of GPCR signaling. To test this hypothesis, we analyzed mice deficient in RGS2, a GTPase-activating protein that greatly accelerates the deactivation rate of heterotrimeric G proteins in vitro. Both rgs2(+/-) and rgs2(-/-) mice exhibited a strong hypertensive phenotype, renovascular abnormalities, persistent constriction of the resistance vasculature, and prolonged response of the vasculature to vasoconstrictors in vivo. Analysis of P2Y receptor-mediated Ca2+ signaling in vascular smooth muscle cells in vitro indicated that loss of RGS2 increased agonist potency and efficacy and slowed the kinetics of signal termination. These results establish that abnormally prolonged signaling by G protein-coupled vasoconstrictor receptors can contribute to the onset of hypertension, and they suggest that genetic defects affecting the function or expression of RGS2 may be novel risk factors for development of hypertension in humans.