Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFβ1 and miR-29 pathways.
Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFβ1 and miR-29 pathways.
复制标题
DOI：
10.1038/srep23010
复制
发表时间：
2016-03-14
影响因子：
4.6
通讯作者：
Pan ZW
中科院分区：
文献类型：
--
作者：
Zhang Y;Wang JH;Zhang YY;Wang YZ;Wang J;Zhao Y;Jin XX;Xue GL;Li PH;Sun YL;Huang QH;Song XT;Zhang ZR;Gao X;Yang BF;Du ZM;Pan ZW
白细胞介素6 （IL-6）已被证明是心脏间质纤维化的重要调节因子。在这项研究中，我们探讨了白细胞介素-6在糖尿病性心肌病发展中的作用及其潜在机制。与链脲佐菌素（STZ）诱导的野生型（WT）糖尿病小鼠相比，IL-6基因敲除小鼠心功能明显改善，间质纤维化明显减轻。IL-6可显著促进培养的心肌成纤维细胞（CFs）的增殖和胶原蛋白的生成。高糖处理增加了胶原蛋白的产生，在IL-6 KO小鼠的CFs中，胶原蛋白的产生得到了缓解。此外，IL-6敲除可减轻糖尿病小鼠心脏和高糖或IL-6处理培养的CFs中tgf - β1的上调。此外，miR-29的表达在IL-6处理后降低，而在IL-6 KO心脏中升高。过表达miR-29阻断IL-6对培养的CFs的促纤维化作用。综上所述，IL-6的缺失能够减轻糖尿病小鼠心肌纤维化，改善心功能。其机制涉及IL-6对tgf - β1和miR-29通路的调控。本研究提示IL-6抑制对伴有纤维化的糖尿病性心肌病的治疗潜力。
Interleukin 6 (IL-6) has been shown to be an important regulator of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-6 in the development of diabetic cardiomyopathy and the underlying mechanisms. Cardiac function of IL-6 knockout mice was significantly improved and interstitial fibrosis was apparently alleviated in comparison with wildtype (WT) diabetic mice induced by streptozotocin (STZ). Treatment with IL-6 significantly promoted the proliferation and collagen production of cultured cardiac fibroblasts (CFs). High glucose treatment increased collagen production, which were mitigated in CFs from IL-6 KO mice. Moreover, IL-6 knockout alleviated the up-regulation of TGFβ1 in diabetic hearts of mice and cultured CFs treated with high glucose or IL-6. Furthermore, the expression of miR-29 reduced upon IL-6 treatment, while increased in IL-6 KO hearts. Overexpression of miR-29 blocked the pro-fibrotic effects of IL-6 on cultured CFs. In summary, deletion of IL-6 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The mechanism involves the regulation of IL-6 on TGFβ1 and miR-29 pathway. This study indicates the therapeutic potential of IL-6 suppression on diabetic cardiomyopathy disease associated with fibrosis.