Bradykinin regulates cell growth and migration in cultured human cardiac c-Kit+ progenitor cells.

Gang Li,Gui-Rong Li,Yan Wang

doi:10.18632/oncotarget.14609

Abstract

Bradykinin is a well-known endogenous vasoactive peptide. The present study investigated the bradykinin receptor expression in human cardiac c-Kit+ progenitor cells and the potential role of bradykinin in regulating cell cycling progression and mobility. It was found that mRNA and protein of bradykinin type 2 receptors, but not bradykinin type 1 receptors, were abundant in cultured human cardiac c-Kit+ progenitor cells. Bradykinin (1-10 nM) stimulated cell growth and migration in a concentration-dependent manner. The increase of cell proliferation was related to promoting G0/G1 transition into G2/M and S phase. Western blots revealed that bradykinin significantly increased pAkt and pERK1/2 as well as cyclin D1, which were countered by HOE140 (an antagonist of bradykinin type 2 receptors) or by silencing bradykinin type 2 receptors. The increase of pAkt, pERK1/2 and cyclin D1 by bradykinin was prevented by the PI3K inhibitor Ly294002, the PLC inhibitors U73122 and neomycin, and/or the PKC inhibitor chelerythrine and the MAPK inhibitor PD98059. Our results demonstrate the novel information that bradykinin promotes cell cycling progression and migration in human cardiac c-Kit+ progenitor cells via activating PI3K, PLC, PKC, cyclin D1, pERK1/2, and pAkt.

Highlights

Cardiac c-Kit+ progenitor cells can potentially differentiate into at least three main cardiac cells, i.e. myocytes, vascular smooth muscle cells and endothelial cells [1], and are believed to be a viable cell source of cell-based therapeutic strategy for treating myocardial ischemia/reperfusion injury in animal models [2,3,4] and patients with ischemic cardiomyopathy [5,6,7,8]
D1 (Figure 9C) was decreased by U73122, neomycin, LY294002, chelerythrine or PD98059. These results suggest that PLC and PI3K are involved in bradykinininduced increase of pAkt, and PLC, PI3K, PKC, and MAPK kinase are involved in the increase of pERK1/2 and cyclin D1 by bradykinin
B2Rs are widely expressed in the heart, brain and spinal cord tissues while the inducible B1Rs are mainly expressed in these organs/tissues under pathophysiological conditions [26, 27]

Summary

Introduction

Cardiac c-Kit+ progenitor cells can potentially differentiate into at least three main cardiac cells, i.e. myocytes, vascular smooth muscle cells and endothelial cells [1], and are believed to be a viable cell source of cell-based therapeutic strategy for treating myocardial ischemia/reperfusion injury in animal models [2,3,4] and patients with ischemic cardiomyopathy [5,6,7,8]. The effect of bradykinin on proliferation of human cardiac c-Kit+ progenitor cells was confirmed by BrdU incorporation assay (Figure 2A).

Results

Conclusion