Resveratrol Attenuates Pressure Overload‐Induced Cardiac Fibrosis and Diastolic Dysfunction via PTEN/AKT/Smad2/3 and NF‐κB Signaling Pathways

Scope Cardiac fibrosis is a key feature of cardiac remodeling. Recently, a protective role for resveratrol (RES) in pressure‐overload‐induced cardiac hypertrophy and contractile dysfunction has been demonstrated. However, the effect of RES on cardiac fibrosis and diastolic function in this model remains unclear. Methods and results Cardiac remodeling is induced in mice by transverse aortic constriction (TAC) for 2–4 weeks. RES is administered at dose of 5 or 50 mg kg–1 d–1 for 2 weeks. It is found that RES administration at 50 mg kg–1 d–1 significantly attenuates TAC‐induced adverse cardiac systolic and diastolic function, fibrosis, inflammation, and oxidative stress via inhibiting PTEN degradation and the downstream mediators. However, RES at 5 mg kg–1 d–1 has no significant effects. RES at 50 mg kg–1 d–1 also ameliorates pre‐established adverse cardiac function and remodeling induced by TAC. Treatment with PTEN inhibitor VO‐OHpic (10 mg kg–1 d–1) for 2 weeks abolishes RES‐mediated protective effects. Additionally, the effect of RES (100 µm) on inhibition of Ang II‐induced fibroblast proliferation and activation in vitro is verified. Conclusions The findings provide new evidence that RES plays a critical role in the progression of cardiac fibrosis and diastolic dysfunction, and suggest that RES may be a promising therapeutic agent for cardiac fibrosis. Cardiac remodeling is induced in mice by transverse aortic constriction (TAC). The results showed that resveratrol administration significantly attenuated TAC‐induced cardiac dysfunction, fibrosis, inflammation, and oxidative stress via inhibiting PTEN degradation and activation of the downstream mediators. Furthermore, a PTEN inhibitor, VO‐OHpic, abolishes resveratrol‐mediated protective effects. These results suggest that resveratrol may be a promising therapeutic agent against cardiac fibrosis.