Bradykinin-mediated Ca2+ signalling regulates cell growth and mobility in human cardiac c-Kit+ progenitor cells

Abstract

Our recent study showed that bradykinin increases cell cycling progression and migration of human cardiac c-Kit⁺ progenitor cells by activating pAkt and pERK1/2 signals. This study investigated whether bradykinin-mediated Ca²⁺ signalling participates in regulating cellular functions in cultured human cardiac c-Kit⁺ progenitor cells using laser scanning confocal microscopy and biochemical approaches. It was found that bradykinin increased cytosolic free Ca²⁺ ( ${\mathrm{Ca}}_i^{2+}$ ) by triggering a transient Ca²⁺ release from ER IP3Rs followed by sustained Ca²⁺ influx through store-operated Ca²⁺ entry (SOCE) channel. Blockade of B2 receptor with HOE140 or IP3Rs with araguspongin B or silencing IP3R3 with siRNA abolished both Ca²⁺ release and Ca²⁺ influx. It is interesting to note that the bradykinin-induced cell cycle progression and migration were not observed in cells with siRNA-silenced IP3R3 or the SOCE component TRPC1, Orai1 or STIM1. Also the bradykinin-induced increase in pAkt and pERK1/2 as well as cyclin D1 was reduced in these cells. These results demonstrate for the first time that bradykinin-mediated increase in free ${\mathrm{Ca}}_i^{2+}$ via ER-IP3R3 Ca²⁺ release followed by Ca²⁺ influx through SOCE channel plays a crucial role in regulating cell growth and migration via activating pAkt, pERK1/2 and cyclin D1 in human cardiac c-Kit⁺ progenitor cells.

Keywords: bradykinin; cell cycle progression; human cardiac c-Kit+ progenitor cells; inositol 1,4,5-triphosphate receptor; migration; store-operated Ca2+ entry.