BNP increases the number of cardiomyocytes in physiological and pathological conditions

Abstract

Brain natriuretic peptide (BNP) treatment protects the heart after myocardial infarction (MI). As cardiomyocytes (CMs) express BNP receptors, the aim of this study was to determine BNP effect on CM's fate in neonatal and in adult infarcted hearts. New born (NB) unmanipulated pups and adult infarcted mice were injected with BNP every 2 days. NB mice were sacrificed eleven days after birth. MI was induced in C57BL/6 and Myh6 MerCreMer mice by permanent ligation of the left anterior descending coronary artery and sacrificed 24 hours and 10 days after surgery. An increased number of CMs was detected in BNP-treated NB mice (+ 18% P = 0.002) and in the infarcted zone (ZI) of adult hearts, 10 days after MI (+ 43%; P = 0.07). In BNP-treated pups, the number of CMs expressing BrdU (+ 22% P = 0.04), phospho histone H3 (pH3) (+ 31%; P = 0.04) and Aurora B (+ 47% P = 0.001) were increased. Expressions of mRNAs coding for cyclins E1 (+ 110% P = 0.01), A2 (+ 126% P = 0.002) and B2 (+70% P = 0.08) were increased in CMs isolated from BNP treated hearts. Accordingly, in vitro BNP treatment of neonatal CMs led to increased number of CMs (+ 21% P = 0.003), and CMs expressing Aurora B (+ 58% P = 0.01), pH3 (+ 75% P = 0.04) or Ki67 (+ 20% P = 0.03). Interestingly, BNP treatment on these cells was associated with p38 MAPK inhibition (-42% P = 0.01). In BNP-treated mice 24 hours after MI, a decreased concentration of cardiac Troponin T in the plasma (− 70% P = 0.04) was measured, whereas the percentage of BrdU+ (+ 92% P = 0.03), pH3+ (+ 51%; n = 2) and Aurora B+ CMs (+ 419% P = 0.03) increased in ZI of BNP-treated hearts, 10 days after MI. In Myh6 MerCreMer mice, the percentage of GFP+ CMs expressing BrdU also increased in ZI (+ 15% P < 0.05). In conclusion, BNP treatment protects CMs from cell death after MI. In addition, it stimulates the proliferation of neonatal and adult pre-existing CMs after MI.