ADAM17 knockdown is more effective than AT1R blocker in alleviating diabetic cardiomyopathy through downregulating the RhoA-ROCK1 pathway

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes that contributes to increased mortality. A-disintegrin and metalloproteinase 17 (ADAM17), a novel member of the renin-angiotensin-aldosterone system (RAAS), has been shown to exert a protective effect against cardiac fibrosis, but the exact molecular mechanisms remain unclear. This study aims to elucidate the role of ADAM17 in the pathogenesis of DCM and its interaction with the RhoA/ROCK1 signaling pathway, focusing on cardiac fibroblast-to-myofibroblast transition and cardiac remodeling. AAV9-mediated gene silencing was used to investigate the effect of ADAM17 silencing on cardiac function and fibrosis in diabetic mice and its advantage over conventional losartan, a selective angiotensin II type 1 receptor (AT1R) antagonist. The results showed that ADAM17 silencing significantly reduced Collagen deposition and pro-fibrotic protein levels. Either ADAM17 knockdown or losartan treatment resulted in less activation of the RhoA/ROCK1 signaling pathway. High glucose induced myofibroblast differentiation, which was inhibited by either treatment. Notably, knockdown of ADAM17 was more effective than losartan in improving cardiac function and reducing fibrosis, but they had no synergistic effect. In conclusion, targeting ADAM17 and RhoA/ROCK1 is a promising therapeutic strategy for the treatment of DCM to improve patient outcomes.

ADAM17; Diabetic cardiomyopathy; Fibrosis; Losartan; Myofibroblast transformation.