Anti-apoptotic, anti-fibrotic, and positive inotropic effects of ghrelin and GHRP on rat and mouse cardiac myocytes

生长激素（GH）是一种由大脑下方的内分泌器官脑下垂体分泌的蛋白质激素。合成GH释放肽（GHRPs）和内源性GHRP （ghrelin）除了释放GH外，还具有许多其他生理功能。ghrp已被证明通过其特定受体影响动物和人类的心脏功能。我们最近在单细胞水平上证明，GHRPs增加心肌细胞的收缩，并保护它们免受心衰和心肌梗死中发生的程序性细胞死亡。我们还证明了GHRPs在慢性心力衰竭中保护心脏，并在实验性心力衰竭模型中减轻心脏功能丧失。现在的初步结果表明，ghrp可以预防心脏纤维化，这是心力衰竭和梗死后心脏功能障碍的原因。本项目拟阐明ghrp在(1)心脏功能增强中的作用机制；(2)抗细胞死亡；(3)体外原代培养大鼠心肌细胞和体内心脏病变小鼠模型的抗纤维化作用。通过完成这个项目，我们将能够(1)更好地了解胃饥饿素在调节心功能中的生理作用；(2)阐明ghrp在治疗慢性心力衰竭方面的潜力，慢性心力衰竭影响澳大利亚1-2%的人口，5年死亡率约为65%。

Growth hormone (GH) is a protein hormone secreted from an endocrine organ, the pituitary gland, below the brain. Synthetic GH-releasing peptides (GHRPs) and endogenous GHRP (ghrelin) possess many other physiological functions in addition to the release of GH. GHRPs have been shown to affect cardiac function in animals and humans through their specific receptors. We recently demonstrated at single cell level that GHRPs increased contraction of cardiac muscle cells and protected them from the programmed cell death which occurs in heart failure and myocardial infarction. We also demonstrated that GHRPs protected the heart in chronic heart failure and alleviated functional loss of the heart in experimental heart failure models. Preliminary results now indicate that GHRPs prevent cardiac fibrosis, which accounts for cardiac dysfunction after heart failure and infarction. It is proposed in this project to clarify the mechanism underlying the action of GHRPs in (1) cardiac functional enhancing; (2) anti-cell death; (3) anti-fibrosis effects, in primary cultured rat myocytes in vitro and in cardiac diseased mouse models in vivo. By completing this project, we will be able to (1) better understand the physiological role of ghrelin in the regulation of cardiac function; and (2) clarify the potential for therapeutic use of GHRPs in the treatment of chronic heart failure, a disease affecting 1-2% of the population of Australia, with 5 year mortality rates about 65%.