IL-6/GP130信号通路介导反Warburg效应调控心肌细胞和心脏成纤维细胞间交互作用及其在糖尿病心肌病代谢重构中的机制研究

糖尿病心肌病（DCM）是糖尿病病人心衰和死亡的主要原因之一，发病机制尚不清楚。我们前期研究发现：高糖引起心肌细胞（CM）GLUT4表达下降而成纤维细胞（CF）GLUT4表达增高；CF糖摄取增加的同时其糖酵解关键酶LDHA表达增加；IL-6/GP130/STAT3通路在CM和CF中均激活，IL-6/GP130抑制剂可增加GLUT4在CM中的表达，降低GLUT4及LDHA在CF中的表达；DCM动物血IL-6增高，心肌STAT3激活；IL-6/GP130抑制剂对DCM动物亦具有保护作用。故我们提出“IL-6/GP130通过介导CF-CM交互，促发反Warburg效应参与DCM发生发展”这一假说，拟进一步阐明CF-CM之间交互作用、乳酸穿梭、心脏代谢重构和结构重构及其与IL-6/GP130/STAT3信号通路之间的内在联系，并探讨靶向抑制IL-6/GP130对DCM的影响，为防治DCM提供新思路。

Diabetic cardiomyopathy (DCM) is one of the leading causes of morbidity and mortality in the diabetic patients, however, currently there is no specific treatment because the underlined mechanism is still unclear. In the preliminary studies we found that high glucose decreased GLUT4 expression in the cardiomyocytes, but meanwhile, increased the expression of GLUT4 in the cardiac fibroblasts. When the uptake of glucose increased in the cardiac fibroblasts, the expression of LDHA in these cells also increased, which exhibited a reverse Warburg effect on the cardiomyocytes. In this process, we also found that IL-6/GP130/STAT3 signaling pathway was highly activated, and importantly, inhibition of this pathway significantly increased GLUT4 expression in the cardiomyocytes, and decreased both GLUT4 and LDHA expression in the cardiac fibroblasts. Furthermore, we found IL-6/GP130/STAT3 signaling pathway was activated in in STZ-induced diabetic mice, as the serum IL-6 level increased at the 10th, 30th, and 60th days after induction, and the STAT3 phosphorylation also significantly increased after induction. Cardiac diastolic function was impaired in these mice, combined with increased fibrosis. Inhibition of IL-6/GP130 by Bazedoxifene improved cardiac function and reduced fibrosis, meanwhile, enhanced autophagy seen in the diabetic mice was also inhibited by Bazedoxifene treatment. Herein, we proposed that the activation of IL-6/GP130 signaling pathway mediates the crosstalk between the cardiac fibrobalsts and the cardiomyocytes, promotes the reverse Warburg effect allowing the intracellular lactate shuttle, which leads to the cardiac metabolic and structural remodeling in DCM. We have designed experiments to investigate this novel mechanism in this proposal, and data from our study will not only help us understand the pathophysiological mechanism of DCM, but also provide new therapeutic options for treatment.