Cardioprotective Effect of Growth Hormone Releasing Hormone

越来越多的人意识到心脏具有多种细胞因子的受体 和生长因子，其活化可增强肌细胞存活和生长。而 生长激素/胰岛素样生长因子1（GH/IGF-1） 轴在调节心脏发育和性能，只是最近， 下丘脑激素，生长激素释放激素也发挥心脏 信号活性，并且GHRH受体存在于肌细胞上。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） 在急性缺血性损伤后刺激实质性心脏修复，而不刺激 与GH轴相关的不良副作用。此外，Granata et al. 证明GHRH（1-44）促进缺血后心肌细胞的存活 再灌注有效的GHRH激动剂的可用性提供了一个主要的新的治疗方法， 机会该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LV功能障碍（啮齿动物和猪，在我们的实验室中使用），以测试 这一假说认为，通过强效激动剂激活心脏GHRH受体可以逆转 重塑和改善心肌梗死后功能恢复 心肌梗死（MI）。我们提出了一个工作计划，以确定作用机制 以及这种效应的表现形式。我们将在三个目标测试以下假设： 检验GHRH-A的作用是由直接受体激活介导的假设 GHRH-R在心脏内的作用;为了检验GHRH-A直接激活 内源性心脏干细胞;研究GHRH激动剂在心肌细胞中的保护作用。 猪心肌梗死模型这一建议对发展一种有前途的新的 预防和逆转MI后重塑的治疗策略。

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.