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 the role of BNP on CM proliferation. We studied the BNP effect on the hearts of new born (NB) and adult infarcted mice. NB mice were injected with BNP and with BrdU two days after birth and sacrificed after eleven days. MI was induced by ligation of the left anterior descending coronary artery. BNP was injected directly into the myocardium after surgery, then intraperitoneally every 2 days. BrdU was added to drinking water. Mice were sacrificed 3 and 10 days after surgery. The infarction zone (ZI) was separated from the rest of the heart (remote zone, RZ). The number of CMs expressing BrdU + (+ 22% P = 0.04) or Aurora B+ (+ 47% P = 0.001) was increased in NB BNP-treated mice compared to the control, leading to increased number of CMs (+ 21%). Expressions of mRNAs coding for the cyclins were also increased in isolated cardiomyocytes from BNP treated hearts: cyclin E1 (+ 110% P = 0.01), A2 (+ 126% P = 0.002) and B2 (+ 70% P = 0.08). In adult infarcted mice, 3 and 10 days after MI, BNP stimulation induced an increased number of BrdU+ CMs and Aurora B + CMs in ZI (3 days: + 172% P < 0.001 and +69% P = 0.01, respectively, 10 days: + 102% P < 0.001 and + 127% P = 0.008, respectively). In parallel, CMs were isolated from NB hearts and cultured with or without BNP. After two weeks of culture, BNP treatment led to increased number of CMs (+ 21% P = 0.003), CMs expressing Aurora B (+ 58% P = 0.01), phospho-histone H3 (+ 75% P = 0.04) and Ki67 (+ 20% P = 0.03). BNP decreased CM binucleation (− 32% P = 0.001). Interestingly, BNP stimulation of CM proliferation in vitro seems to be trigger by the p38 MAPK pathway inhibition (− 42% P = 0.01). BNP treatment leads to increased number of proliferating CMs in vivo in NB hearts and in adult hearts after MI. Whether this reflects an increase of cytokinesis remains to be established in vivo.
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