糖尿病心肌损害新机制：PEDF调控脂肪酸代谢参与心肌脂毒性

Our previous studies have demonstrated that PEDF is an important regulator of lipid metabolism, and involved in the development of hyperlipidemia and hepatic lipidosis in obese mice. Moreover, PEDF has also been proved to play a key role in the pathological process of insulin resistance induced by obesity. Recently, we also found that PEDF gene knockout can significantly induce the increasing of blood FFAs, and result in heart dysfunction and the decreased ejection fraction of left ventricular. High free fatty acids and its metabolic disorders in organs have been proved to be an important cause of insulin resistance and diabetic myocardial damage. Thus, we hypothesize that PEDF may affect myocardial lipid deposition and excessive fatty acid oxidation, and relate with the myocardial damage induced by lipotoxicity in the pathological of diabetes. Based on the above research, we choose diabetic animal models induced by STZ chemical or established by genetic methods, and aim for the reliable evidence that PEDF is involved in the metabolic disorders of fatty acids and diabetic myocardial damage induced by lipotoxicity by the technologies of gene modification, metabolic molecular labeling, molecular biological and morphological methods, and in vitro & in vivo. We hope to investigate the biological values and the molecular mechanisms of PEDF in the development of diabetic cardiomyopathy in more details, and form our own new academic opinions on PEDF and diabetic cardiomyopathy. Moreover, the current project will provide new targets and theoretical basis for the diagnosis and treatment of the major diseases such as cardiovascular diseases and diabetes.

前期我们证实PEDF是重要的脂肪代谢调节分子，参与肥胖时高脂血症形成和脂肪肝的发生。PEDF还被证实在肥胖诱发胰岛素抵抗中发挥重要作用。最近，我们又发现PEDF基因敲除能显著升高血FFAs水平，并导致小鼠心脏射血分数降低和左心室功能下降。高游离脂肪酸及其代谢障碍，被认为是引发胰岛素抵抗及糖尿病心肌损害的重要原因。由此，我们分析，糖尿病时PEDF可能影响心肌脂质沉积和脂肪酸过度氧化，并在多个环节上参与了脂毒性诱导心肌细胞损害。基于上述研究基础，本课题拟以化学诱导和遗传性糖尿病模式动物为研究对象，借助体内外实验和基因修饰、代谢分子标记、分子生物学、形态学等技术和方法，旨在获得PEDF参与脂肪酸代谢紊乱和脂毒性致糖尿病心肌细胞损害的可靠证据，证实PEDF在糖尿病心肌病发生、发展中的生物学价值，并深层次解析其分子机制，形成新的学术观点，为心血管疾病、糖尿病等相关重大疾病诊治提供新的靶点和理论基础。

目前越来越多的研究关注到PEDF对脂肪酸代谢的调控作用及其在相关疾病中发挥的功能，而PEDF是否参与糖尿病性心肌损伤仍不清楚。.本项目中，我们证实：相对非肥胖型二型糖尿病小鼠，肥胖型二型糖尿病小鼠显示出急剧爆发的心肌脂毒性，这导致其伴随更严重的心脏结构重塑和更早发生的心脏收缩功能障碍。更重要的是，研究结果提示，PEDF在肥胖型与非肥胖型二型糖尿病心脏中的表达差异，可能是导致两者心肌代谢差异的关键因素。进一步的研究结果表明：在肥胖型二型糖尿病早期，心肌和循环PEDF显著升高，而在肥胖型二型糖尿病后期发生心脏功能障碍时，心肌和循环PEDF则急剧下降；PEDF敲除小鼠表现出显著的肥胖、高血脂、高血糖和胰岛素抵抗表型，而PEDF过表达则可以改善肥胖型二型糖尿病小鼠的上述表型；PEDF敲除小鼠表现出显著的心脏结构重塑和心脏功能障碍，而PEDF过表达则可以改善肥胖型二型糖尿病小鼠的上述表型；PEDF敲除小鼠表现出显著的心肌脂毒性，而PEDF过表达则可以改善肥胖型二型糖尿病小鼠的心肌脂毒性；PEDF敲除小鼠表现出显著的心肌PPARα通路激活和胰岛素信号通路抑制，而PEDF过表达则可以逆转肥胖型二型糖尿病小鼠心肌的上述通路改变。因此，PEDF在肥胖型2型糖尿病心肌损伤的发生发展中具有保护作用，其机制主要包括抑制心肌PPARα通路以降低脂毒性和激活心肌胰岛素信号通路以改善胰岛素抵抗。.综上所述，本项目首次较全面的揭示了肥胖型和非肥胖型二型糖尿病小鼠心肌病变的病理生理学差异，并首次证明了PEDF调控心肌脂毒性和胰岛素抵抗在糖尿病性心肌病中的作用和机制，研究结果有助于我们更深刻的了解肥胖型2型糖尿病和非肥胖型二型糖尿病心肌病变在心脏结构、功能、代谢和分子机制中的差异，并有助于研究者和临床医生更加全面的认识PEDF在脂毒性、胰岛素抵抗和糖尿病心肌损害发生发展中的作用和价值，为脂毒性、胰岛素抵抗诱导糖尿病心肌损害增添新的理论依据，为心血管疾病、糖尿病等重大疾病的防治策略提供重要靶点和理论基础。