Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFβ1 and miR-29 pathways.

Yang Zhang,Jin Wang,Jing-Hao Wang,Zhi-Ren Zhang,Gen-Long Xue,Xiao-Tong Song,Peng-Hui Li,Ying-Zhe Wang,Yi-Yuan Zhang,Yi-Lin Sun,Xue-Xin Jin,Zhi-Min Du,Bao-Feng Yang,Xu Gao,Zhen-Wei Pan,Qi-He Huang,Yue Zhao

doi:10.1038/srep23010

Abstract

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.

Highlights

Myocardial fibrosis is formed mainly due to the excessive proliferation of cardiac fibroblasts and the increased collagen synthesis and deposition
We found that EF, FS and early to late mitral inflow velocity (E/A) ratio were all significantly decreased in the wild-type DM mice than wild-type controls, indicating the impairment of cardiac function (Fig. 2A–C)
In this study we demonstrated that Interleukin 6 (IL-6) knockout is protective against Diabetic cardiomyopathy (DCM)

Summary

Introduction

Myocardial fibrosis is formed mainly due to the excessive proliferation of cardiac fibroblasts and the increased collagen synthesis and deposition. Inflammatory cytokines have been shown to be critical factors in regulating fibroblast proliferation, collagen secretion and interstitial fibrosis[6]. Meléndez GC et al demonstrated that IL-6 treatment increased collagen production in cultured cardiac fibroblasts and promoted interstitial fibrosis of rat heart in vivo[8]. In the cardiac tissue of streptozotocin (STZ) induced diabetic mice the expression of certain fibrotic-related microRNAs such as miR-2112, miR-2413, and miR-2914 were altered, implying that miRNAs may be involved in the pathogenesis of DCM by affecting fibrosis. We hypothesized that IL-6 may regulate interstitial fibrosis of diabetic hearts by changing the expression of certain fibrotic-related miRNAs. In this study, we found that knockout of IL-6 alleviated the interstitial fibrosis and improved cardiac function in STZ induced diabetic mice. We confirmed that IL-6 regulates the proliferation and collagen synthesis by inhibiting TGFβ 1 and miR-29 pathways

Methods

Results

Conclusion