| First Author | Zhao B | Year | 2022 |
| Journal | Cardiovasc Res | Volume | 118 |
| Issue | 8 | Pages | 1947-1963 |
| PubMed ID | 34324657 | Mgi Jnum | J:335111 |
| Mgi Id | MGI:7378621 | Doi | 10.1093/cvr/cvab234 |
| Citation | Zhao B, et al. (2022) Resistin deletion protects against heart failure injury by targeting DNA damage response. Cardiovasc Res 118(8):1947-1963 |
| abstractText | AIMS: Increased resistin (Retn) levels are associated with development of cardiovascular diseases. However, the role of Retn in heart failure (HF) is still unclear. Here we probed the functional and molecular mechanism underlying the beneficial effect of Retn deletion in HF. METHODS AND RESULTS: Wild-type (WT) and adipose tissue-specific Retn-knockout (RKO) mice were subjected to transverse aortic constriction (TAC)-induced HF. Cardiac function and haemodynamic changes were measured by echocardiography and left ventricular catheterization. Adipose tissue Retn deletion attenuated while Retn cardiac-selective overexpression, via a recombinant adeno-associated virus-9 vector, exacerbated TAC-induced hypertrophy, cardiac dysfunction, and myocardial fibrosis in WT and RKO mice. Mechanistically, we showed that Gadd45alpha was significantly increased in RKO HF mice while cardiac overexpression of Retn led to its downregulation. miR148b-3p directly targets Gadd45alpha and inhibits its expression. Retn overexpression upregulated miR148b-3p expression and triggered DNA damage response (DDR) in RKO-HF mice. Inhibition of miR148b-3p in vivo normalized Gadd45alpha expression, decreased DDR, and reversed cardiac dysfunction and fibrosis. In vitro Retn overexpression in adult mouse cardiomyocytes activated miR148b-3p and reduced Gadd45alpha expression. Gadd45alpha overexpression in H9C2-cardiomyoblasts protected against hydrogen peroxide- and Retn-induced DDR. CONCLUSION: These findings reveal that diminution in circulating Retn reduced myocardial fibrosis and apoptosis, and improved heart function in a mouse model of HF, at least in part, through attenuation of miR148b-3p and DDR. The results of this study indicate that controlling Retn levels may provide a potential therapeutic approach for treating pressure overload-induced HF. |
