Azilsartan ameliorates ventricular hypertrophy in rats suffering from pressure overload-induced cardiac hypertrophy by activating the Keap1–Nrf2 signalling pathway

Objectives Investigate if azilsartan protects against myocardial hypertrophy by upregulating nu- clear factor erythroid 2-related factor 2 (Nrf2)-mediated pathways. Methods Abdominal aortic constriction (AAC)-induced cardiac hypertrophy in rats was applied. Azilsartan or vehicle was administered daily for 6 weeks in sham or AAC rats. Cardiac morphology and ventricular function were determined. Azilsartan effects upon neonatal rat cardiomyocyte (NRCM) hypertrophy and molecular mechanisms were studied in angiotensin (Ang) II-stimulated NRCMs in vitro. Nrf2-small interfering RNA (siRNA) was used to knockdown Nrf2 expression. Messenger RNA (mRNA)/protein expression of Kelch-like erythroid cell-derived protein (Keap)1 and Nrf2 and its downstream antioxidant enzymes was determined by real-time reverse transcrip- tion–quantitative polymerase chain reaction and western blotting, respectively. Key findings Azilsartan treatment ameliorated cardiac hypertrophy/fibrosis significantly in AAC rats. Azilsartan increased expression of Nrf2 protein but decreased expression of Keap1 protein. Upregulation of protein expression of Nrf2’s downstream antioxidant enzymes by azilsartan treat- ment was observed. Azilsartan inhibited Ang II-induced NRCM hypertrophy significantly and similar effects on the Keap1–Nrf2 pathway were observed in vivo. Nrf2 knockdown markedly coun- teracted the beneficial effects of azilsartan on NRCM hypertrophy and the Keap1–Nrf2 pathway. Conclusions Azilsartan restrained pressure overload-induced cardiac remodelling by activating the Keap1–Nrf2 pathway and increasing expression of downstream antioxidant enzymes to alleviate oxidative stress.