A12686 The sirtuin 6 attenuates myocardial injury and dysfunction by regulating ADAM17/ACE2 pathway in hypertensive rats

Objectives: The sirtuin 6 (SIRT6) is an important modulator of cardiovascular functions in health and diseases. However, the exact role of SIRT6 in hypertension is poorly defined. Methods: The male Sprague-Dawley rats were used to the normal control or randomized to preparation of hypertensive rats by Ang II (200 ng/kg/min) infusion with treatment of recombinant pAAV-SIRT6 or pAAV-GFP for 4 weeks. Results: There were reduced expression of SIRT6 and ACE2, and augmented levels of TGF-β, osteopontin (OPN), MMP-2 and MMP-9 in hypertensive rats, contributing to elevated cardiac fibrosis and exacerbated ultrastructural injury. Enhanced phosphorylation of ADAM-17 and impaired heart function were observed in both hypertensive rats and ACE2 knockout rats, characterized by increased LVPWT. Treatment of pAAV-SIRT6 significantly prevented Ang II-mediated pressor response and attenuated myocardial fibrosis and ultrastructural injury in hypertensive rats. These changes were associated with marked increases in LVEF and LVFS as well as downregulated levels of OPN, MMP-2 and MMP-9 in hypertensive rats. In cultured neonatal rat cardiac fibroblasts, exposure of Ang II resulted in reduction in ACE2 expression and phosphorylation of p-ADAM-17 as well as increases in cellular proliferation and migration, which were rescued by treatment of pAAV-SIRT6. Conclusion: The SIRT6 prevents hypertension-mediated pathological hypertrophy, impaired heart function and ultrastructural injury in hypertensive rats. These results indicate cardiac protective roles of SIRT6 in the prevention of cardiac dysfunction and injury via activation of ADAM-17-ACE2 pathway and suppression of the TGF-β-OPN signaling. Targeting SIRT6 and ACE2 has potential therapeutic importance for controlling myocardial injury and dysfunction in hypertension.