Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
J Cell Physiol. 2021 May;236(5):3481-3494. doi: 10.1002/jcp.30078. Epub 2020 Sep 28.
Cardiac fibrosis is one of the main pathological manifestations of diabetic cardiomyopathy (DCM). Cardiac fibroblast activation is a key effector of cells resulting in diabetic cardiac fibrosis. However, the underlying mechanism of cardiac fibroblast activation and diabetic cardiac fibrosis remains unclear. Accumulating evidence suggests that DNA methylation alterations play a central role in cardiac fibroblast activation. In this study, we demonstrated that DNA methyltransferase 1 (DNMT1)-mediated suppression of cytokine signaling 3 (SOCS3) promoter hypermethylation leads to downregulation of SOCS3 expression in diabetic cardiac fibrosis. High glucose-induced expression of DNMT1 was increased in cardiac fibroblasts, while the expression of SOCS3 was decreased. Downregulation of SOCS3 facilitated activation of STAT3 to promote cardiac fibroblast activation and collagen deposition. Genetic or pharmacological inactivation of DNMT1 reversed the activated phenotype of cardiac fibroblasts. Clinically, we observed a significant inverse correlation between DNMT1 and SOCS3 expression levels, and loss of SOCS3 expression or increased expression of DNMT1. Taken together, these findings identify DNMT1 silencing of SOCS3 axis as a driver of cardiac fibroblast activation in diabetic cardiac fibrosis. These results provide a scientific and new explanation of the underlying mechanism of diabetic cardiac fibrosis.
心肌纤维化是糖尿病心肌病（DCM）的主要病理表现之一。心脏成纤维细胞的激活是导致糖尿病性心肌纤维化的关键效应细胞。然而，心脏成纤维细胞激活和糖尿病性心肌纤维化的潜在机制尚不清楚。越来越多的证据表明，DNA 甲基化改变在心脏成纤维细胞激活中起着核心作用。在这项研究中，我们证明了 DNA 甲基转移酶 1（DNMT1）介导的细胞因子信号转导 3（SOCS3）启动子超甲基化的抑制导致糖尿病性心肌纤维化中 SOCS3 表达下调。高葡萄糖诱导的心脏成纤维细胞中 DNMT1 的表达增加，而 SOCS3 的表达减少。SOCS3 的下调促进了 STAT3 的激活，从而促进心脏成纤维细胞的激活和胶原沉积。DNMT1 的遗传或药理学失活逆转了心脏成纤维细胞的激活表型。临床上，我们观察到 DNMT1 和 SOCS3 表达水平之间存在显著的负相关，SOCS3 表达缺失或 DNMT1 表达增加。综上所述，这些发现确定了 DNMT1 沉默 SOCS3 轴是糖尿病性心肌纤维化中心脏成纤维细胞激活的驱动因素。这些结果为糖尿病性心肌纤维化的潜在机制提供了科学的新解释。
