DNA methyltransferase-1 inactivation of androgen receptor axis triggers homocysteine induced cardiac fibroblast autophagy in diabetic cardiac fibrosis.

Diabetic cardiac fibrosis is one of the main pathological manifestations of diabetic cardiomyopathy (DCM). Cardiac fibroblast autophagy plays critical roles in diabetic cardiac fibrosis, however, the underlying mechanism of cardiac fibroblast autophagy and diabetic cardiac fibrosis still largely unknown. The aim of the study was to investigate the mechanism of DNMT1 mediated DNA methylation alterations control cardiac fibroblast autophagy in diabetic cardiac fibrosis. We employed streptozotocin (STZ)-induced rats DCM, DCM patient and Hcy induced cardiac fibroblast autophagy. Heart tissue sections were stained with H&E, Sirius Red and Masson's trichrome stain. The expression of DNMT1, AR, Collagen genes mRNA was detected by qRT-PCR. MSP and BSP detected the methylation status of the AR promoter. The expression of DNMT1, AR, Collagen and autophagy-related proteins were detected by Western blotting, Immunofluorescence, Immunohistochemistry. Gain and loss function of AR and DNMT1 in cardiac fibroblast was analyzed. DNMT1 inhibition or knockdown elevated the expression of AR in cardiac fibroblast. Furthermore, we found that AR negatively regulation of Hcy induced cardiac fibroblast autophagy. We demonstrated that DNMT1 enhances cardiac fibroblast autophagy in diabetic cardiac fibrosis through inhibiting AR axis. In conclusion, our results provide new insight into the DNMT1 inactivation of AR axis triggers cardiac fibroblast autophagy in diabetic cardiac fibrosis.

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