Brain natriuretic peptide improves heart regeneration after infarction by stimulating cardiomyocyte renewal

Abstract

ABSTRACTAimBrain Natriuretic Peptide (BNP) supplementation after infarction increases heart function and decreases heart remodeling. BNP receptors, NPR-A and NPR-B, are expressed on adult cardiomyocytes (CMs). We thus investigated whether a part of the BNP cardioprotective effect in infarcted and unmanipulated hearts is due to modulation of the CM fate.Methods and ResultsBNP was injected in infarcted adult mice and in unmanipulated neonatal and adult mice. CMs were isolated, counted and characterized.Increased number of CMs was detected in the hypoxic area of infarcted hearts, and in unmanipulated neonatal and adult hearts after BNP treatment. Accordingly, Troponin T plasma concentration was significantly reduced 1 and 3 days after infarction in BNP-treated mice, demonstrating less CM death. Furthermore, higher number of small, dedifferentiated and mononucleated CMs were identified in adult BNP-treated hearts when compared to saline-treated hearts. BNP-treated CMs express higher levels of mRNAs coding for hif1 alpha and for the different cyclins than CMs isolated from saline-treated hearts. Higher percentages of CMs undergoing DNA synthesis, expressing Ki67, phospho histone3 and Aurora B were detected in all BNP-treated hearts, which suggests that BNP stimulates CMs to re-enter to the cell cycle. Results in vitro confirmed that BNP stimulates the proliferation of the neonatal CMs and the dedifferentiation of the adult CMs.BNP effect on adult CMs in vivo is mediated by NPR-A binding and activation of the ERK MAP kinase pathway. Interestingly, increased number of CMs was also detected in adult infarcted hearts treated with LCZ696, which inhibits all natriuretic peptide degradations.ConclusionsAltogether, our results identified BNP and all therapies aimed to increase BNP’s bioavailability (such as LCZ696 treatment) as new targets to increase heart regeneration. By protecting CMs from cell death, and by stimulating their proliferation, BNP treatment leads to increased number of CMs in neonatal, adult unmanipulated and infarcted hearts.