Hexarelin对心血管系统的保护作用及其机制研究

【作者】 庞锦江；

【导师】 许荣焜； 曹济民； 陈孟勤； 陈晨；

【作者基本信息】 中国协和医科大学 ， 生理学， 2004， 博士

【摘要】 合成的生长激素释放肽具有很强的促生长激素释放作用，还有许多其它生物活性。最近研究发现，肽类的GHS有明显的心血管作用。本实验选用合成的生长激素释放肽之一hexarelin，通过离体和在体实验，从整体、细胞、分子水平研究了hexarelin对心力衰竭过程心肌细胞凋亡、心肌细胞肥大、以及对动脉粥样硬化的影响。首先，在第一、二部分实验，我们以离体和在体实验，研究了hexarelin对Ang Ⅱ诱导的原代培养新生乳鼠心肌细胞凋亡的作用和四种GHRP对心衰大鼠心肌细胞凋亡的影响。结果表明，hexarelin可明显抑制Ang Ⅱ诱导的心肌细胞凋亡，而且四种GHRP对压力负荷型心衰大鼠的心功能有明显改善作用，对心衰时心肌细胞的凋亡有明显抑制作用。其作用机制可能与抑制caspase-3酶活性，抑制bax mRNA的表达，增加bcl-2 mRNA表达，抑制p38MAPK蛋白表达有关。鉴于GHRP对心衰大鼠有明显治疗作用，而心肌细胞肥大是心力衰竭的重要发病过程之一，在第三部分我们观察了hexarelin对Ang Ⅱ诱发的心肌细胞肥大的作用以及hexarelin对SHR心肌肥厚的作用。结果提示hexarelin有明显抗Ang Ⅱ诱发的心肌细胞肥大和抑制SHR心肌肥厚的作用。其作用机制与抑制AT1受体mRNA表达和上调AT2受体mRNA的表达，抑制ERK1／2的活性有关。从前三部分实验结果可见，hexarelin对心血管系统中的肾素-血管紧张素系统有明显影响，提示hexarelin对动脉粥样硬化的发生发展可能也有重要作用。因此在第四部分，我们观察了hexarelin对动脉粥样硬化大鼠的影响和对AngⅡ诱发的血管平滑肌细胞增殖的作用。结果显示，hexarelin有明显的抗动脉粥样硬化作用，其机制可能与增加血清HDL-c，NO，减少LDL-c，减少主动脉中脂质和钙的沉积，抑制Ang Ⅱ诱发的血管平滑肌细胞增殖密切相关，还可能与CD36 mRNA的表达上调有关。在离体和在体状态下，给予GHRP或hexarelin，都可以明显上调GHS-R mRNA的表达，提示hexarelin的心血管保护作用还可能与GHS-R mRNA的表达增加有关。更多还原

【Abstract】 Synthetic growth hormone releasing peptides possess strong growth hormone-releasing effects and effusive peripheral activities. Recently, several independent observations indicated that GHRP exerts cardiovascular activities. We investigated the effects of hexarelin on cardiomyocyte apoptosis in rats with heart failure, cardiac hypertrophy and atherosclerosis in in vivo and in vitro models. At first, the effects of hexarelin on cardiomyocyte apoptosis induced by Ang II, and effects of four GHRPs (GHRP-1, GHRP-2, GHRP-6, hexarelin) on cardiomyocyte apoptosis in pressure-over load heart failure rat model were observed in part I and part II. The results showed that (1) hexarelin inhibited cardiomyocyte apoptosis induced by AngII; (2) GHRPs improved cardiac dysfunction and inhibit the cardiomyocyte apoptosis in rats with heart failure. These results indicated that hexarelin abates cardiomyocytes from Ang II-and heart failure-induced cardiomyocyte apoptosis in rat. The possible mechanisms were possibly via inhibiting the activity of caspase-3, inhibiting bax mRNA expression, increasing the expression of bcl-2 mRNA and inhibiting the expression of p38MAPK protein. (3) Hexarelin inhibited cardiomyocyte hypertrophy induced by Ang II and inhibit the cardiac hypertrophy of SHR. The mechanisms of the antihypertrophy effect of hexarelin may be associated with inhibition of ATI receptor mRNA expression, with upregulation of the expression of AT2 receptor mRNA and ERK1/2 activity. As hexarelin could affect the renin-angiotensin system, with the inhibition of hexarelin may have effect on the development of atherosclerosis. We investigated the effect of hexarelin on the astherosclerosis model of rat and the effect of hexarelin on proliferation of vascular smooth muscle cell(VSMC) induced by Ang II. (4) Hexarelin showed obvious antiatheosclerosis effects. The underlying mechanisms may related with the increasing of serum HDL-c and NO, the decreasing of serum LDL-c, the attenuate of accumulation of lipid and calcium deposits in aorta and the inhibition of VSMC proliferation induced by Ang II. These effects of GHRP may be also associated with the upregulation of CD36 mRNA. Taken together, administration of更多还原