Natriuretic Peptide Receptor B modulates the proliferation of the cardiac cells expressing the Stem Cell Antigen-1

Abstract

Brain Natriuretic Peptide (BNP) injections in adult “healthy” or infarcted mice led to increased number of non-myocyte cells (NMCs) expressing the nuclear transcription factor Nkx2.5. The aim of this study was to identify the nature of the cells able to respond to BNP as well as the signaling pathway involved. BNP treatment of neonatal mouse NMCs stimulated Sca-1+ cell proliferation. The Sca-1+ cells were characterized as being a mixed cell population involving fibroblasts and multipotent precursor cells. Thus, BNP treatment led also to increased number of Sca-1+ cells expressing Nkx2.5, in Sca-1+ cell cultures in vitro and in vivo, in the hearts of neonatal and adult infarcted mice. Whereas BNP induced Sca-1+ cell proliferation via NPR-B receptor and protein kinase G activation, CNP stimulated Sca-1+ cell proliferation via NPR-B and a PKG-independent mechanism. We highlighted here a new role for the natriuretic peptide receptor B which was identified as a target able to modulate the proliferation of the Sca-1+ cells. The involvement of NPR-B signaling in heart regeneration has, however, to be further investigated.

Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+epicardium-derived cells

“…1A). This protocol from our previous studies demonstrated that BNP injections (first intraventricular and then intraperitoneal) reduced heart remodelling and increased Sca-1 + cell numbers 16,26 . However, as BNP modulates the function of different organs (kidneys, vessels, pancreas), its effect on hearts could be indirect.…”

“…Non-myocyte cells (NMCs) were isolated from the hearts of neonatal C57BL/6, NPR-A KO or NPR-B KO pups (1-2 days) as previously described 16,26 and were cultured in medium composed of MEM Alpha (Gibco 32571-028), 10% FBS, 100 U/ml penicillin G, 100 µg/ml streptomycin with or without BNP (5 µg/ml) up to confluence (i.e., 10-11 days). Adult cardiac NMCs were isolated from adult C56BL/6 mice (6-8 weeks old) by digesting adult ventricles in buffer containing 1 mg/ml collagenase IV (Gibco 17104-019) and 1.2 mg/ml dispase II (Sigma, D4693) and were cultured in EGM™-2 Endothelial Cell Growth Medium-2 BulletKit (Lonza, CC-3162) supplemented with 15% fetal calf serum (FCS) (invitrogen Corp) with or without BNP (5 µg/ml) up to confluence (i.e., 5-10 days).…”

“…Although BNP treatment inhibits fibrosis and protects cardiomyocytes from cell death, the cellular mechanisms responsible for this cardioprotective effect have not been fully elucidated 16,17,24 . Curiously, we observed that BNP stimulates in vitro and in vivo (i.e., in adult infarcted hearts) the proliferation of cardiac nonmyocyte cells (NMCs) expressing the stem cell antigen-1 (Sca-1) 26 . As Sca-1 + cells in adult hearts were reported to be pure endothelial cells 27 , we questioned whether BNP modulates endothelial cell fate.…”

“…The NPR-A (−/−) mice were kindly provided by Dr Feng Li and Prof Nobuyo Maeda (Chapel Hill, North Carolina, US). The NPR-B deficient mouse strain (C57BL/6J-Npr2 slw ) was generated as heterozygous mice in the Laboratory of Animal Resource Bank at NationalInstitute of Biomedical Innovation (Osaka, Japan)16,26 . FUCCI (Fluorescence Ubiquitin Cell Cycle Indicator) mice were provided by Prof Marlene Knobloch29 .…”

Natriuretic Peptides: The Case of Prostate Cancer

“…However, some groups [ 38 , 52 , 53 , 54 ] reported that plasma BNP levels are elevated in patients with cancer and suggested that these increases are due to the cardiac response to cancer-related inflammation. Indeed, BNP is upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in myocardiocytes [ 55 ] and patients with hematologic malignancies have elevated levels of N-terminal –proBNP, related to a possible myocardium response to the setting of the cancer [ 56 , 57 ]. Serum levels of N-terminal pro- C-type NP are associated with bone formation activity in patients with multiple myeloma [ 58 ], and act on mice lung fibroblasts to reduce pulmonary fibrosis [ 59 ].…”