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

TL;DR

Protosappanin A protects the heart from damage by reducing stress and inflammation through a key pathway called Nrf2.

Contribution

This study is the first to show that Protosappanin A reduces heart damage via Nrf2 activation.

Findings

PTA improved heart function and reduced cell enlargement and fibrosis in mice with heart stress.

PTA reduced oxidative stress and cell death (pyroptosis) in heart cells.

Nrf2 inhibition blocked the protective effects of PTA, confirming its role in the mechanism.

Abstract

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 Caesalpinia sappan, has been shown to confer significant protective effects against multiple cardiovascular insults. However, its precise role in pressure overload-induced pathological cardiac hypertrophy remains elusive.

In the present study, a mouse model was established through transverse aortic constriction (TAC) surgery and then intragastrically administered with PTA for 4 weeks.

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).

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.

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