网膜素-1下调致肌浆网-线粒体对话异常促发糖尿病心肌病及机制

The morbidity of diabetic cardiomyopathy (DCM) is greatly increasing in recent years and the prognosis is poor, so it is urgent to elucidate the molecular etiology mechanisms. Omentin-1 is a new adipokine found recently which regulates metabolism and insulin sensitivity. Clinical studies have shown that the decrease of omentin-1 is associated with obesity and diabetes mellitus. Our latest preliminary experiments showed that the serum levels of omentin-1 were decreased and DCM occurred in type 2 diabetic mice, and the administration with exogenous omentin-1 could partially reverse the detrimental cardiac changes; there were also cardiac remodeling and dysfunction in omentin-1 knockout (OMT-/-) mice. Further preliminary experiments showed that myocardial fibrosis, cardiomyocytes apoptosis, cytoplasmic phospholipase A2 (cPLA2) levels, acid sphingomyelinase (aSMase) activity and ceramide were increased in diabetic mice. Omentin-1 inhibited the release of cytochrome c from mitochondria and decreased the intercellular calcium transport from the sarcoplasmic reticulum to mitochondria in high glucose/high-fat cultured cardiomyocytes, whereas ceramide analogues blocked these effects. These results suggested the close association between omentin-1 and DCM. Based on this data, we will test the hypothesis that downregulation of circulating omentin-1 levels contributes to pathogenesis of DCM through cPLA2/aSMase/ceramide pathway-mediated disturbance of sarcoplasmic reticulum–mitochondria crosstalk (calcium transport) and apoptosis. This project is expected to reveal the novel mechanisms for DCM pathogenesis.

糖尿病心肌病(DCM)发病率高且预后差，亟需阐明分子病因学机制。网膜素-1是近年新发现的脂肪因子，可调节代谢和胰岛素敏感性。临床研究表明，网膜素-1降低与肥胖及糖尿病等相关。申请者新近预实验显示，2型糖尿病小鼠血清网膜素-1降低，且发生DCM，补充网膜素-1可部分逆转心肌改变；网膜素-1敲除小鼠(OMT-/-)也存在心脏重塑和功能障碍。进一步预实验显示，糖尿病小鼠心肌纤维化与细胞凋亡、胞浆型磷脂酶A2(cPLA2)、酸性鞘磷脂酶(aSMase)活性及神经酰胺增加；网膜素-1抑制高糖/高脂培养心肌细胞的细胞色素C释放，减少Ca2+从肌浆网向线粒体转运，神经酰胺类似物可阻断之。提示网膜素-1与DCM的密切联系。本课题拟在此基础上验证网膜素-1下调促发DCM的假设、并研究其机制是否与cPLA2/aSMase/神经酰胺途径影响肌浆网-线粒体对话(钙转运)而促凋亡有关，期望揭示DCM发生的新机制。

在本项目资助下，所获主要科学发现如下：①发现网膜素-1表达缺陷可能通过cPLA2依赖的aSMase/神经酰胺途径致内质网–线粒体对话异常，诱导心肌细胞凋亡，增加心肌纤维化，从而促发糖尿病心肌病。②发现网膜素-1下调可诱导肥胖相关的微动脉内皮功能障碍及血压升高，中药何首乌的有效活性成分二苯乙烯苷（TSG）可促进网膜脂肪组织表达和分泌网膜素-1，改善微血管氧化应激，部分恢复微血管内皮功能从而发挥降压效应，提示TSG可能作为一种代谢异常相关高血压的候选治疗药物具有开发价值。③发现胎球蛋白B（FetB）介导的胰岛素受体β（IRβ）酪氨酸磷酸化水平降低及其下游信号激活减少，是糖尿病心肌缺血易损性增加的原因之一。④发现Tribbles homolog 3（TRIB3）上调可诱导肺动脉胰岛素抵抗（VIR）而促发低氧性肺动脉高压，提示改善血管胰岛素敏感性可能有助于限制低氧性肺动脉高压的进展。⑤发现C1q/TNF相关蛋白-9（CTRP9）通过调节AMPK介导的内皮素-1和一氧化氮间的平衡，改善低氧诱导的大鼠肺动脉高压。自项目实施以来，所获科研成果有：上述研究结果发表5篇SCI论文、2篇中文源核期刊综述，5人次在国际会议做壁报交流，1人次全国会议交流做口头报告，并获中国生理学会青年优秀报告者奖，申请发明专利4项，副主编专著1部、参编教材和专著3部，培养博士生2人获得学位、另有博士后1人和硕士生4人在读。项目负责人入选空军高层次科技人才、军队优秀专业技术人才三类岗位津贴，担任中国病理生理学会机能实验教学工作委员会委员、陕西省生理科学会常务理事、《生理学报》和《心脏杂志》编委、以及38个SCI期刊的审稿人。