DNMT1 deregulation of SOCS3 axis drives cardiac fibroblast activation in diabetic cardiac fibrosis

Abstract

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.

Deciphering Obesity-Related Gene Clusters Unearths SOCS3 Immune Infiltrates and 5mC/m6A Modifiers in Ossification of Ligamentum Flavum Pathogenesis

“…Tao et al. found DNMT1 silencing of SOCS3 axis as a driver of cardiac fibroblast activation in diabetic cardiac fibrosis ( 53 ). Yu et al.…”

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

“…We can make informed assumptions and infer the involvement of specific cell types which do play an active role in tissue-specific co-expression networks ( 124 ). ATM is mainly found in endothelial and epithelial cells ( 125 , 126 ), FGFR1 in fibroblasts and epithelial cells ( 57 , 58 ), FBXW7 in hepatic stellate mesenchymal, mononuclear and pulmonary epithelial stem cells ( 60 – 62 ), ESR1 in myofibroblasts and epithelial cells ( 63 , 64 ), CCND1 in renal glomerular mesangial and hepatic stellate cells ( 66 , 127 ), HIF1A in renal epithelial cells and cardiac fibroblasts ( 68 , 128 ), CEBPB in hematopoietic and renal epithelial cells ( 70 , 71 ), NAMPT in hepatic stellate and renal glomerular mesangial cells ( 72 , 129 ), IRF1 in renal epithelial cells ( 76 ), SOCS1 in hepatocytes and macrophages ( 78 ), SOCS3 in cardiac fibroblasts ( 90 ), ICAM1 in endothelial cells ( 79 ), ETS1 in hepatic stellate and renal epithelial cells ( 130 , 131 ), IL7R in hepatic stellate cells ( 82 ), MMP1 in fibroblasts ( 83 , 132 ), HNF4A in hepatocytes ( 85 ), CCL2 in fibroblasts ( 86 , 133 ), CASP1 in hepatic endothelial cells ( 87 ) and STAT1 in macrophages ( 88 , 89 ). HSP90B1 , although it has been recently reported to be implicated in fibrosis ( 92 ), the specific cell type expressing it, still, remains undetermined.…”

Epigenetics Approaches toward Precision Medicine for Idiopathic Pulmonary Fibrosis: Focus on DNA Methylation

“…DNMTs have exhibited their essential roles in multiple organ fibrosis. The DNMT1-mediated suppression of cytokine signaling 3 (SOCS3) leads to the deregulation of STAT3 to promote cardiac fibroblast activation and collagen deposition in diabetic cardiac fibrosis [ 69 ]. The down-regulation of SOCS3 promotes the activation of STAT3-related fibroblast-to-myofibroblast transition.…”