PEDF/PEDF-R诱导急性缺血心肌细胞进入“冬眠状态”的作用及相关机制研究

Data indicate that the survived hibernating myocardium (HM) is an adaptive response of the myocardial cells to sustained myocardial ischemia after acute myocardial infarction (AMI) and existence of the HM will also serve as a reserve of own myocardial cell for functional recovery of the ischemic hearts that undergo the revascularization therapy subsequently. Therefore, we put forward a new idea that protects the ischemic myocardial cells (IMCs) and reduces their death during the acute phase of myocardial ischemia, inducing survived IMCs to enter a "hibernating state". This new strategy may have a great value for improving curative effect and prognosis of AMI patients who undergo the revascularization therapy..Our pre-experiment had evidenced that PEDFR mediated-PEDF (pigment epithelium-derived factor) significantly protected rat IMC against apoptosis and programmed necrosis. We hypothesize that PEDF enhances anti-oxidative stress effect of IMCs and induces the survived IMCs to develop an adaptive structural and functional remodeling with lower energy consumption and enter "hibernating state" subsequently. The possible mechanism is that PEDF activates lipase and phospholipase A2 attached on PEDFR to augment the levels of intracellular signaling molecules FFAs, DAG and LPA, which activate the related signaling pathways, respectively. .In this study, we will verify this novel scientific hypothesis and elucidate its related mechanisms at the cellular and animal levels, providing useful experimental evidence to innovate therapy strategy for treatment of the ischemic heart disease.

研究表明，冬眠心肌是心肌细胞对急性心肌梗死（AMI）后持续缺血的适应性反应，也是AMI后续血运重建疗效及心脏功能恢复重要的细胞基础。如能在缺血急性期，保护缺血心肌细胞，诱导心肌细胞进入“冬眠状态”，对AMI患者血运重建后心脏功能的改善将具有重要的临床意义。预实验证实，色素上皮衍生因子（PEDF）具有抗缺血心肌细胞凋亡和程序性坏死的细胞保护作用。.假设：PEDF通过增强细胞抗氧化能力，促使细胞发生结构及功能适应性重塑、降低细胞能量消耗，从而诱导急性缺血心肌细胞进入“冬眠状态”；其机制与PEDF激活PEDF受体（PEDF-R）脂肪酶和磷脂酶A2活性，增加心肌细胞内信使分子LPA、FFAs和DAG含量，继而分别激活相关信号通路有关。.本课题将在细胞和动物水平，深入探讨PEDF-R介导PEDF诱导急性缺血心肌细胞进入“冬眠状态”的作用，并阐明其相关机制，为缺血性心脏病治疗策略的创新提供实验依据。

冬眠心肌（HM）是心肌细胞对急性心肌梗死（AMI）后持续缺血的适应性反应，也是AMI后续血运重建疗效及心脏功能恢复重要的细胞学基础。在缺血急性期，诱导心肌细胞进入“冬眠状态”，保护缺心肌细胞，对AMI患者血运重建后心脏功能的改善及恢复具有重要的临床意义。.本项目科研团队以往的研究证实，色素上皮衍生因子（PEDF）不仅是心脏中不可或缺的内源性调节因子，同时也是重要的心脏保护因子。本项目在细胞和动物水平，深入研究了（1）PEDF 是否诱导急性缺血心肌细胞进入“冬眠状态；（2）PEDF-R是否介导 PEDF 诱导急性缺血心肌细胞进入“冬眠状态”；（3）PEDF-R 介导PEDF诱导急性缺血心肌细胞进入“冬眠状态”的相关分子机制。.研究结果表明，（1）PEDF-R介导PEDF，通过PLN去磷酸化降低细胞内Ca2+水平，快速诱导降低缺氧心肌细胞收缩力，减少ATP消耗，增加缺血心肌能量储备，改善大鼠缺血心脏功能；（2）PEDF增加缺氧心肌细胞PA及DAG含量，活化PKC-α，通过PKC/ULK1/ FUNDC1/LC3通路，促进线粒体自噬并降低线粒体密度，提高缺氧心肌细胞存活率；（3）PEDF-R介导PEDF，经PI3K-AKT通路，促进GLUT4膜转位，增加缺氧心肌细胞葡萄糖摄取，发挥心肌保护作用；（4）在动物整体水平验证，PEDF可诱导急性缺血心肌进入“冬眠样”状态，维持缺血心肌细胞活性。.本研究项目深入探讨了PEDFR介导PEDF诱导急性缺血（氧）心肌细胞发生环境适应性结构及功能重塑的作用，充分阐明了相关分子机制；在动物整体水平，验证PEDFR/PEDF诱导急性缺血心肌细胞快速转化为“冬眠样心肌”的可行性。本项目研究成果对创新缺血性心脏病心肌保护方法及相关治疗策略，将具有重要的理论意义及潜在的应用价值。