锌调控CARD9/BCL10/p38α MAPK通路预防肥胖相关性心肌病的机制研究

Obesity related cardiomyopathy (ORC) impacts the living quality of diabetic patients seriously. Our previous studies showed that Zinc deficiency exacerbates while Zinc supplement attenuates ORC, respectively. Meanwhile, the activation of p38 MAPK and the expression of CARD9/BCL10 were increased in the ORC. These effects were worsened by Zinc deficiency and attenuated by Zinc supplement, respectively. Administration of a p38 MAPK specific inhibitor completely abolished the ORC in obese mice in vivo. Inhibition of p38 MAPK with its specific siRNA prevented ANP up-regulation in vitro. In addition, Zinc can increase cardiac MT expression. Therefore, we propose that Zinc may induce MT expression to decrease CARD9 expression and formation of complex with BCL10 to active p38α MAPK-mediated cardiac remodeling. To test this hypothesis, the CARD9-KO、MT-KO transgenic mice will be used to investigate the cardiac prevention by Zinc of the development of ORC, to define the mechanisms by which Zinc prevents the ORC via up-regulating MT to effectively suppress CARD9 and/or BLC10 expression and complex formation, and subsequent activation of p38α MAPK-mediated cardiac remodeling pathway. This project will provide the theoretic foundation for Zinc to be clinically used in future.

肥胖相关性心肌病（ORC）是肥胖的主要并发症之一,严重影响患者的生活质量.前期研究工作中我们发现, 低锌加重肥胖小鼠的ORC,而补锌可以改善ORC.同时ORC小鼠心肌中CARD9, BCL10,p38 MAPK磷酸化水平明显上调,低锌及补锌可以分别加重或者减轻上述表现.体内和体外实验分别应用p38 MARK抑制剂和p38αMAPK siRNA抑制p38αMAPK表达后显著减少肥胖小鼠心肌中ANP的表达水平,从而减轻ORC.此外,通过外源性补锌明显增加肥胖小鼠心肌中MT的表达.据此推测,锌可能通过上调MT抑制了CARD9/BCL10/p38αMAPK通路,改善了ORC的发生和发展.为验证假说,本课题拟应用CARD9-KO,MT-KO转基因小鼠诱导肥胖模型,深入探讨锌改善ORC的机理和机制,为锌防治ORC提供实验基础和理论依据.

肥胖相关性心肌病（ORC）是肥胖的主要并发症之一，严重影响患者的生活质量。此研究工作中我们应用原代心肌细胞给予棕榈酸处理，应用BCL10siRNA处理后，CARD9和ANP以及3-NT/4-HNE明显下调；MT-KO小鼠原代心肌细胞棕榈酸处理后BCL10/CARD9/p38MAPK明显下调，阐明锌通过上调MT抑制了CARD9/BCL10/p38MAPK通路，改善了ORC的发生和发展。同时，应用阿霉素处理肥胖小鼠，发现阿霉素进一步恶化肥胖小鼠的心脏损伤，本课题深入探讨了锌改善ORC的机理和机制，为锌防治ORC提供实验基础和理论依据。