Does BNP modulate cardiomyocyte proliferation?

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 newborn (NB) and adult infarcted mice. NB mice were injected with BNP and with BrdU two days after birth. Eleven days post-birth, the mice were sacrificed. 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 up to 10 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. In addition, the total number of CMs was also increased (+21%) in BNP-treated mice. After MI, the number of BrdU + CMs and the number of Aurora B + CMs were increased in ZI, 3 days after MI in BNP-treated hearts compared to the infarcted untreated hearts (+172%, P < 0.001; +69%, P = 0.01, respectively). This seems to be also the case 10 days after MI in ZI for the BrdU + CMs (preliminary results: +194%, n = 2 mice/group). In parallel, we isolated CMs from the hearts of NB. These cells were cultured with or without BNP. After two weeks of culture with BNP, the number of Aurora B + CMs increased (+87%, P = 0.003) but not the number of binucleated CMs. In addition, among Aurora B + CMs, BNP increased the number of cells undergoing cytokinesis (+6%). Interestingly, the total number of CMs was increased in BNP-treated cells compared to control (+26%, P = 0.01). BNP treatment leads to increased number of Aurora B + CMs in vivo in NB hearts, and in adult hearts after MI. This was confirmed by in vitro studies. Whether this reflects an increase of cytokinesis remains to be established in vivo.