0006 : Proliferation of the cardiac precursor cells expressing the stem cell antigen-1 is controlled by activation of the natriuretic peptide receptors

Abstract

A part of the cardioprotective role of the Brain Natriuretic Peptide (BNP) in mouse hearts is due to its effect on the cardiac precursor cell (CPC) proliferation and differentiation. Thus, in this study we identified the CPC subset able to respond to BNP as well as the signaling pathway involved. We demonstrated by immunohistochemistry and by flow cytometry analysis that the c-kit + and the Sca-1 + cell subsets in neonatal and adult murine hearts express the NPR-A and NPR-B receptors and are thus able to be stimulated by BNP. In vitro , BNP only stimulated the proliferation of the Sca-1 + cells and not of the c-kit + cells. Among Sca-1 + cells, BNP treatment led to increased number of Sca-1 + Nkx2.5 + cells, which were able to differentiate into cardiomyocytes. To determine by which receptor BNP acts on Sca-1 + cells to stimulate their proliferation, cells were isolated from neonatal hearts of mice deficient for the NPR-A (NPRA-KO) or NPR-B receptor. BNP stimulated the proliferation of the Sca-1 + NPR-A KO cells but not of the Sca-1 + cells lacking the NPR-B receptor, demonstrating that Sca-1 + cell proliferation is linked to NPR-B activation. This was confirmed by stimulating the Sca-1 + cells by the C-Natriuretic Peptide able also to activate the NPR-B receptor. BNP binding to NPR-B receptor led in Sca-1 + cells to Protein Kinase G activation and increased phosphorylation of phospholamban and p38. Reducing PKG activation inhibited BNP-induced-Sca-1 + cell proliferation, whereas reducing p38 phosphorylation increased Sca-1 + cell proliferation after BNP treatment. Phosphorylation of p38 was not mediated by BNP binding to NPR-B receptor but by its binding to NPR-A. In this work, we identified the Sca-1 + cells as being the targets of BNP in vitro and in vivo. BNP via NPR-B binding and PKG activation clearly stimulated the proliferation of the CPCs expressing Sca-1. Interestingly, is the dual role of the NPR-A and NPR-B receptors which control Sca-1 + cell proliferation. The author hereby declares no conflict of interest