Omega-3多不饱和脂肪酸对糖尿病性心肌病保护作用机制的研究

Diabetic cardiomyopathy (DCM) is widespread focal necrosis of the myocardium caused by cardiac microvascular disease and myocardial metabolic disorder in diabetic patients, different from cardiac impairment induced by the alcoholic, functional and coronary factors. Exploring the mechanism of DCM occurrence and development would help to find effective treatment strategies, which would improve the prognosis of the diabetic patient, and have important clinical significance. Polyunsaturated fatty acids (PUFA) and metabolic enzymes are important mediators for various pathophysiological phenomena during the development and progression of DCM. The comprehensive exploration of DCM metabolic profile is conducive to the systematic understanding of DCM, provide possible therapeutic targets in the clinic, rescue the cardiac function of diabetic patients and Improve long-term prognosis of patients. Preliminary research results suggest that the serum concentration of AA, DHA, EPA, and DPA in the DCM group are lower than those in the health group. Besides, the concentration of LOX metabolites is higher, while the concentration of COX and CYP450 metabolites is lower in DCM group than in health group. This study is to explore the metabolic profile of PUFA in DCM patients, find the highly correlated Omega-3 PUFA metabolites or metabolic enzymes, and explore the relevant molecular mechanisms, in order to provide new therapeutic Strategy of DCM.

糖尿病心肌病（DCM）是糖尿病引起心脏微血管病变和心肌代谢紊乱所致的心肌广泛局灶性坏死，有别于酒精性、功能性及冠脉因素引起的心脏功能损害，探究DCM发生、发展的机制，寻找有效的治疗策略，对改善糖尿病患者的预后具有重要的临床意义。多不饱和脂肪酸（PUFA）及代谢酶是DCM发生、发展过程中多种病理生理现象的重要介质。对于DCM代谢谱的全面认知，有利于系统了解DCM病理机制，寻找可能的靶点，为临床提供可行的治疗思路，最大限度的挽回糖尿病患者心功能，提高糖尿病患者的远期获益。前期研究结果提示，与健康对照组相比，DCM组患者AA、DHA、EPA、DPA的表达水平下降。LOX代谢产物表达水平升高，而COX、CYP450代谢产物表达水平下降。本课题拟探究DCM患者PUFAs代谢谱的特点，寻找与DCM高度相关的Omega-3 PUFA代谢产物或代谢酶，并深入挖掘相关分子机制，为DCM临床治疗提供新的思路。

糖尿病性心肌病（Diabetic cardiomyopathy, DCM）是糖尿病引起心脏微血管病变和心肌代谢紊乱所致的心肌广泛局灶性坏死。早期主要表现为心肌缺血加重后发生的舒张功能紊乱，即射血分数保留的心力衰竭（Heart failure with preserved ejection fraction, HFpEF）。面对DCM带来的日益增多的医疗资源需求，亟需针对HFpEF患者的治疗方案。而现有的心衰治疗办法，对于DCM的治疗效果有限。多不饱和脂肪酸（Polyunsaturated fatty acids, PUFAs）是DCM发生、发展过程中多种病理生理现象的重要介质。环氧-二十碳三烯酸（Epoxyeicosatrienoic acids, EETs）在体内的浓度主要由sEH调节，并参与心血管系统的多种内源性调节过程，具有多种心脏保护作用，通过调节sEH活性，获得稳定浓度的EETs水平，将有可能为DCM提供新的治疗方案，为临床提供可行的治疗思路，最大限度的挽回糖尿病患者心功能，提高糖尿病患者的远期获益。本研究通过质谱检测，在下游代谢产物（DHETs）水平相当的前提下，DCM患者血浆中的EETs水平明显高于对照组。已有研究指出，DHET/EET比例可用来评估sEH活性。该研究中DCM的DHET/EET比例显著高于对照组患者。表明DCM患者体内，EETs通过sEH水解的作用较对照组显著增强，提示DCM病程中sEH活性显著增高。代谢组学分析表明，抑制sEH活性对HFpEF具有治疗潜能。本研究前期合成了一系列sEH抑制剂并建立DCM小鼠模型，应用sEH抑制剂后小鼠的心室舒张功能明显改善，并通过改善心肌肥大、纤维化和氧化应激水平对心肌组织带来保护性作用。深入的机制探讨发现，sEH抑制剂通过改善HFpEF小鼠心脏脂质代谢紊乱，进而改善心脏舒张功能。