Protosappanin A protects against pathological cardiac hypertrophy by inhibiting oxidative stress and NLRP3 inflammasome-mediated pyroptosis via activation of the Nrf2 signaling pathway.

Introduction: Pathological cardiac hypertrophy is a pivotal pathological process underlying various cardiac diseases, including heart failure (HF). Protosappanin A (PTA), a major biphenyl compound isolated from Methods: In the present study, a mouse model was established through transverse aortic constriction (TAC) surgery and then intragastrically administered with PTA for 4 weeks. Results: Our results indicate that PTA treatment led to an improvement in cardiac contractile function, a reduction in cardiomyocyte hypertrophy, and an attenuation of myocardial fibrosis in TAC-operated mice. Notably, PTA exerted its anti-hypertrophic actions by mitigating myocardial oxidative stress injury and inhibiting cardiomyocyte pyroptosis. Nevertheless, the above cardioprotective effects of PTA were largely abrogated by the use of the nuclear factor erythroid 2-related factor 2 (Nrf2) specific inhibitor ML385 in TAC-treated mice or Nrf2 siRNA in angiotensin II (Ang II)-treated neonatal mouse cardiomyocytes (NMCMs). Discussion: Our study demonstrates for the first time that PTA ameliorates cardiac remodeling and dysfunction in mice with pathological cardiac hypertrophy by suppressing oxidative stress and cardiomyocyte pyroptosis through activating of the Nrf2 signaling pathway, highlighting additional therapeutic option for clinical prevention and treatment of HF patients.