Brain natriuretic peptide is able to stimulate cardiac progenitor cell proliferation and differentiation in murine hearts after birth

Abstract

Brain natriuretic peptide (BNP) contributes to heart formation during embryogenesis. After birth, despite a high number of studies aimed at understanding by which mechanism(s) BNP reduces myocardial ischemic injury in animal models, the actual role of this peptide in the heart remains elusive. In this study, we asked whether BNP treatment could modulate the proliferation of endogenous cardiac progenitor cells (CPCs) and/or their differentiation into cardiomyocytes. CPCs expressed the NPR-A and NPR-B receptors in neonatal and adult hearts, suggesting their ability to respond to BNP stimulation. BNP injection into neonatal and adult unmanipulated mice increased the number of newly formed cardiomyocytes (neonatal: +23 %, p = 0.009 and adult: +68 %, p = 0.0005) and the number of proliferating CPCs (neonatal: +142 %, p = 0.002 and adult: +134 %, p = 0.04). In vitro, BNP stimulated CPC proliferation via NPR-A and CPC differentiation into cardiomyocytes via NPR-B. Finally, as BNP might be used as a therapeutic agent, we injected BNP into mice undergoing myocardial infarction. In pathological conditions, BNP treatment was cardioprotective by increasing heart contractility and reducing cardiac remodelling. At the cellular level, BNP stimulates CPC proliferation in the non-infarcted area of the infarcted hearts. In the infarcted area, BNP modulates the fate of the endogenous CPCs but also of the infiltrating CD45(+) cells. These results support for the first time a key role for BNP in controlling the progenitor cell proliferation and differentiation after birth. The administration of BNP might, therefore, be a useful component of therapeutic approaches aimed at inducing heart regeneration.

Ablation of periostin inhibits post-infarction myocardial regeneration in neonatal mice mediated by the phosphatidylinositol 3 kinase/glycogen synthase kinase 3β/cyclin D1 signalling pathway

“…We found that, in this strain of neonatal mice subjected to MI, periostin deficiency impaired the regenerative capacity of cardiomyocytes. Similar results were described by others using non-cardiovascular disease models, with recent studies showing that periostin promoted pancreatic exocrine regeneration and neural stem cell proliferation 34 , 35 …”

“…We found that, in neonatal mice, myocardial ANP was downregulated at 7 days after MI but was upregulated at 21 d. Schoensiegel et al 38 reported that plasma levels of the N-terminal propeptide of ANP were not increased in adult mice subjected to non-ischaemic MI for 4 weeks. In a recent report by Bielmann et al , 35 BNP stimulated cardiac progenitor cell proliferation and differentiation in murine hearts after birth and BNP administration induced heart regeneration. Becker et al 39 also demonstrated in vitro that ANP induced proliferation of neonatal murine cardiomyocytes.…”

Protective effect of lyophilized recombinant human brain natriuretic peptide on renal ischemia/reperfusion injury in mice

“…After BNP treatment, the number of renal tubular epithelial cells increased by approximately 5%. This result is consistent with the finding that BNP is able to stimulate cardiac progenitor cell proliferation and differentiation in murine hearts after birth (Bielmann et al, 2015), which indicates that BNP can also promote the proliferation of renal tubular epithelial cells. Furthermore, our results showed that serum Scr and BUN levels significantly decreased in the BNP + I/R group compared with the I/R group.…”

Factors for C-Kit Expression in Cardiac Outgrowth Cells and Human Heart Tissue

“…A recent study demonstrated that BNP stimulates the differentiation of cardiac progenitor cells into cardiomyocytes in vitro, and that injection of BNP into the mouse heart increases the number of newly formed cardiomyocytes. 24) According to our results, serum BNP was the only factor that was associated with the increased expression of c-kit in native cardiac tissue and the c- tissue and in expanded cells: Conflicting results have been reported regarding differences in stem cell activity among different regions of the heart. Some reports have suggested that the main source of CSCs is the atrium, 13) especially the RA appendage; 9,12) however, another study demonstrated the opposite result.…”