Isorhynchophylline enhances Nrf2 and inhibits MAPK pathway in cardiac hypertrophy

Isorhynchophylline (IRN) is one of the major tetracyclic oxindole alkaloids found in Uncaria rhynchophylla. Studies have found that IRN has diverse biological activities including antioxidant, anti-apoptosis, and neuroprotection. However, little is known about the effect of IRN on the development of cardiac hypertrophy. In this study, we investigated the change of the cell surface area and nascent protein synthesis of cultured H9c2 cardiomyocytes on exposure to phenylephrine (PE) plus IRN, and thus confirmed that IRN ameliorated cardiomyocyte hypertrophy induced by PE in vitro. Meanwhile, it turns out that IRN is also effective in neonatal rat ventricular myocytes (NRVMs) stimulated with angiotensin II (AngII). We also showed that IRN prevented cardiac dysfunction in mice with pressure overload due to transverse aortic constriction (TAC) and attenuated cardiac hypertrophy and fibrosis. IRN treatment improved the cardiac function assessed by echocardiographic parameters fractional shortening (FS) as well as suppressed the cardiac hypertrophy phenotypes, such as the increasing of ventricular mass/body weight and myocyte cross-sectional area. RT-PCR analysis showed that IRN treatment also alleviated the expression of fetal genes of ANP, BNP, Myh7, and the correlated fibrosis genes including TGF-β1, collagen I, collagen III, and CTGF in vivo. Meanwhile, IRN had anti-oxidative effects on cardiac remodeling with suppressed 4-HNE and MDA. Western blot analysis showed that the Nrf2 nuclear translocation and MAPK pathway were involved in the potential mechanisms of IRN on cardiac hypertrophy inhibition. The results of our study provide further evidence that IRN is a promising drug for the treatment of cardiac hypertrophy.