Cardioprotective Effect of Growth Hormone Releasing Hormone

人们越来越意识到心脏有多种细胞因子的受体。 和生长因子，它们的激活可以促进心肌细胞的存活和生长。而当 人们对生长激素/胰岛素样生长因子1(GH/IGF-1)很感兴趣。 AXIS在心脏发育和性能的调节中，直到最近才 认识到下丘脑激素、生长激素释放激素也能发挥心脏作用 GHRH受体存在于心肌细胞上。最近，我们 证明了一种有效的生长激素释放激素激动剂(GHRH-A：JI-38) 无刺激性急性缺血损伤后应激性实质性心脏修复 与生长激素轴相关的不良副作用。此外，Granata et al. GHRH(1-44)促进缺血后心肌细胞存活 再灌流。强大的GHRH激动剂的可获得性提供了一种主要的新疗法 机会。这个项目的总体目标是使用经过充分验证的动物模型 缺血性损伤和左心功能障碍(我们实验室正在使用的啮齿动物和猪)测试 强效激动剂激活心脏GHRH受体可逆转的假说 重塑和改善心肌梗死后功能恢复 心肌梗死(MI)。我们提出了一项工作计划，以确定行动机制 以及这种效应的表现形式。我们将在三个目标中检验以下假设： 检验GHRH-A效应是通过直接受体激活介导的假设 心脏内的GHRH-R；检验GHRH-A直接激活的假设 内源性心脏干细胞；研究GHRH激动剂对急性心肌梗死的保护作用 心肌梗死猪模型。这项建议对开发一种有前途的新的 预防和逆转心肌梗死后重构的治疗策略。

There is growing awareness that the heart has receptors for a wide range of cytokines and growth factors, activation of which can enhance myocyte survival and growth. While there has been interest in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis in the regulation of cardiac development and performance, only recently is it appreciated that the hypothalamic hormone, GH releasing hormone also exerts cardiac signaling activity, and that the GHRH receptor is present on myocytes. Recently, we demonstrated that a potent growth hormone releasing hormone agonist (GHRH-A: JI-38) stimulated substantial cardiac repair following acute ischemic injury without stimulating unwanted side effects associated with the GH axis. In addition, Granata et al. demonstrated that GHRH(1-44) promotes survival of cardiomyocytes following ischemia reperfusion. The availability of potent GHRH agonists offers a major new therapeutic opportunity. The overall goal of this project is to use well-validated animal models of ischemic injury and LV dysfunction (rodent and porcine, in use in our laboratory) to test the hypothesis that activation of cardiac GHRH receptors by potent agonists can reverse remodeling and improve recovery of functional performance following myocardial infarction (MI). We propose a program of work to determine the mechanism of action and manifestations of this effect. We will in three aims test the following hypothesis: To test the hypothesis that the effects of GHRH-A are mediated by direct receptor activation of the GHRH-R within the heart; To test the hypothesis that GHRH-A directly activates endogenous cardiac stem cells; Investigate the protective effects of GHRH agonist in a pig model of MI. This proposal has major implications for developing a promising new treatment strategy for the prevention and reversal of remodeling following MI.