Ghrelin通过miR-208家族调控UCP2表达改善心衰心肌代谢重构的机制研究

能量代谢紊乱是心功能不断恶化的因素并可能成为新的治疗靶点，Ghrelin是调节能量代谢的促生长激素释放多肽。我们前期研究发现Ghrelin可通过下调AT1受体抑制心肌重构；下调影响能量代谢的线粒体内膜解偶联蛋白2 (UCP2)可改善心肌重构；我们还在心衰心肌的高通量测序中发现miRNA-208存在差异性表达，且有研究表明其可通过AT1受体参与心肌重构。我们假设Ghrelin可通过miRNA-208家族调控UCP2并改善由AT1受体介导的能量代谢紊乱。我们将建立动物实验模型及细胞实验，采用基因沉默/过表达等方法探究心衰心肌miRNA-208家族成员与UCP2下调的关系及对心肌代谢重构的影响，通过细胞转染沉默相关基因及特异性阻断剂明确Ghrelin受体（GHSR1a/GHS-R1b）及受体后PI3K/Akt通路对miRNA-208家族的调控作用，进一步揭示ghrelin的抗心衰作用。

Energy metabolisc disorder plays a role in cardiac function deterioration and may become the new target for treatment of heart failure. The growth hormone–releasing peptide ghrelin could regulate energy metabolism. Our previous studies have found that ghrelin could inhibit myocardial remodeling by down-regulating Ang II type 1 (AT1) receptor expression. Myocardial remodeling could be significantly attenuated by down-regulating the expression of mitochondrial uncoupling protein 2 (UCP2), which was found to be a regulator of myocardial energy metabolism. By high-throughput sequencing, microRNA-208 was found to be expressed differently in myocardial tissue between heart failure and normal rats. Moreover, studies have shown that miR-208 was involved in myocardial remodeling through regulating the AT1 receptor. There for, we assume that ghrelin improves the energy metabolism disorders mediated by AT1 receptor via regulate the UCP2 expression through miR-208. In this study, the rat model of heart failure will be established and the primary rat cardiomyocytes will be cultured, gene silencing, gene overexpression and other methods will be used to explore the relationship of miR-208 family members and the UCP2 expression, and the influence on myocardial metabolic remodeling. Silencing specific genes with siRNA or application specific blocker will be used to clear the readjustment of ghrelin receptors (GHSR1a/GHS - R1b) and PI3K/Akt pathway on miR-208, which will further reveal the anti-heart failure mechanisms of ghrelin.