Dual-specificity phosphatase 19 alleviates cardiac hypertrophy via inhibiting ASK1 phosphorylation

Abstract Dual-specificity phosphatase 19 (DUSP19) negatively regulates MAPK pathway and has become a promising target for treating spinal cord injury and osteoarthritis. However, the function and underlying mechanism of DUSP19 in cardiac hypertrophy remain unclear. Our study observed that DUSP19 was significantly upregulated in cardiomyocytes stimulated with angiotensin-II and hypertrophic hearts. In vitro, knockdown of DUSP19 significantly aggravated cardiomyocytes hypertrophy induced by angiotensin-II, whereas DUSP19 overexpression ameliorated hypertrophy. In vivo, overexpression of DUSP19 using AAV9 gene-transfer attenuated cardiac hypertrophy, fibrosis, ventricular dilation and dysfunction induced by pressure overload. Mechanistically, DUSP19 overexpression blocked the phosphorylation of ASK1 and its downstream pathway (JNK and p38), whereas knockdown of DUSP19 activated the ASK1/p38-JNK pathway. Moreover, we found that DUSP19 directly bound to ASK1. In addition, ASK1 inhibitor reversed the exaggerated cardiomyocytes hypertrophy induced by DUSP19 knockdown. This study suggested that DUSP19 negatively regulate cardiac hypertrophy induced by pressure overload through inactivation of ASK1/p38-JNK and may provide new therapeutic target for myocardial hypertrophy.