Ghrelin通过拮抗血管紧张素II抑制心衰心肌细胞凋亡的机制研究

Ghrelin and its receptors (GHS-R1a, GHS-R1b) are widely distributed in cardiovascular tissues, and GHS-R1a and GHS-R1b may mediate different biological effects on the heart. Ghrelin can be administered to treat chronic heart failure (CHF). However, the underlying mechanism of ghrelin anti-heart failure effects remains unclear. Our previous studies have shown that ghrelin can inhibit myocardial apoptosis of rats with heart failure in vivo, and was accompanied by angiotensin II (Ang II) type 1 receptor (AT1R) down-regulated. We also found that ghrelin can inhibit Ang II-induced cardiomyocyte apoptosis by down-regulating AT1R, thereby plays the role of anti-heart failure. These results suggest that ghrelin may play the cardiovascular protective effects through blocking the effects of Ang II. To further verify the above reasoning and its mechanism, in the study, we will observe effects of ghrelin on Ang II and its receptors in different stages of heart failure. Further, take cardiomyocyte apoptosis as a research target, we intend to explore the role of GHS-R1a and GHS-R1b in ghrelin inhibiting myocardial apoptosis in heart failure through blocking or silencing GHS-R1a and GHS-R1b actions in vitro and in vivo. In addition, we will block the PI3K signaling pathway by PI3K antagonist after the ghrelin receptor to clarify whether ghrelin inhibit cardiomyocyte apoptosis by PI3K/Akt signaling pathway in heart failure. As a result, findings of the study will provide new targets on alleviating ventricular remodeling and treatment of heart failure.

促生长激素释放多肽(Ghrelin)及其介导不同生物学作用的GHS-R1a、GHS-R1b型受体广泛存在于心血管系统,可改善心功能,但其机制不明。我们前期工作发现Ghrelin在体内实验可抑制心衰大鼠心肌细胞凋亡,并伴有血管紧张素II (Ang II) 1型受体下调;Ghrelin在体外实验可抑制Ang II诱导的心肌细胞凋亡,提示Ghrelin可能通过拮抗Ang II发挥抗心衰效应。为进一步验证上述推论并探讨其机制,本研究拟观察在心衰不同时期Ghrelin对Ang II及其受体的作用;并以心肌细胞凋亡为研究靶点,拟于在体与离体实验分别阻断或沉默GHS-R1a、GHS-R1b的作用,在受体水平探讨Ghrelin抑制心衰心肌细胞凋亡的机制;并进一步用特异性拮抗剂阻断PI3K的作用,在受体后水平明确Ghrelin是否通过PI3K/Akt信号通路抑制心衰心肌细胞凋亡,为心衰治疗提供新靶点。

促生长激素释放多肽(Ghrelin)具有多种心血管保护作用，然而其对心衰的作用及机制均不明确。本研究深入探讨了Ghrelin对心衰不同时期心功能的影响及机制，明确了Ghrelin对心衰不同时期心功能的影响；明确了Ghrelin对心衰不同时期心肌梗死面积的影响；明确了Ghrelin改善心梗后心衰大鼠心功能的可能机制：抑制心梗后心衰大鼠心肌细胞凋亡；明确了Ghrelin抑制心肌细胞凋亡的可能机制：增加Bcl-2/Bax比值，抑制内质网应激反应；明确了Ghrelin抑制内质网应激的可能机制：①抑制心衰时AngII过度表达，②下调AT1R，而对AT2R无明显影响；明确了Ghrelin抑制AngII表达，下调AT1R表达的可能机制：Ghrelin可通过上调Ghrelin受体GHSR-1a及GHSR-1b表达，进而通过PI3K信号分子下调AT1R表达，抑制Ang II诱导的心肌细胞凋亡。以上问题的阐明，对阐明心衰机制、寻找治疗心衰的新靶点具有重要意义。.本课题取得成果如下：项目资助已发表SCI论文4篇（尚有4篇SCI文章待发表），核心论文3篇；本课题协助培养硕士研究生1名，尚有3名博士研究生预计2018年6月答辩。课题负责人以本课题的研究成果作为心衰网络调控机制的一部分，于2016年度申报并获得吉林省科学技术进步奖一等奖。