A Novel Mechanism of Salvianolic Acid B in Postmyocardial Infarction Cardiac Protection: PHB1-Driven Raf-ERK Pathway Activation Promotes Cardiomyocyte Mitosis

Abstract

Heart failure (HF) following myocardial infarction remains a leading cause of global morbidity and mortality, necessitating novel therapeutic strategies. Salvianolic acid B (SalB), one of the major active components of Salvia miltiorrhiza Bunge, has been shown to effectively reverse ischemia-induced myocardial infarction and improve cardiac function. Here, we report a novel mechanism by which SalB treats postmyocardial infarction heart failure by promoting cardiomyocyte re-entry into the cell cycle. A novel protein target of SalB, Prohibitin 1 (PHB1), was identified using chemical biology techniques. Experiments involving overexpression and knockdown of PHB1 have demonstrated that SalB promotes cardiomyocyte mitosis by acting on PHB1, which in turn upregulates the phosphorylation level of the Raf-ERK pathway. Molecular dynamics simulations provide a comprehensive explanation for the mechanism by which SalB enhances Raf phosphorylation. The findings reveal that SalB binds to the C-terminal of PHB1/2 heterodimer, inducing a conformational change that enhances Raf-ERK pathway activation via Akt-mediated phosphorylation, thereby promoting cardiomyocyte mitosis. The findings of this study propose a promising new molecular mechanism through which SalB can contribute to the preservation and restoration of cardiac function.

Keywords

cell cycle / cardiomyocyte proliferation / Prohibitin 1 / Raf-ERK pathway / salvianolic acid B

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