Ischemia‐Reperfusion Induces Transcriptional Activation of Brain Natriuretic Peptide Gene via ERK1/2 in H9c2 cells.

Abstract

Brain natriuretic peptide (BNP) is a cardiac hormone released from heart ventricular cells in response to myocyte stretch. Although BNP has recently been shown to be cardioprotective during myocardial ischemia/reperfusion (IR), mechanism of BNP gene expression by IR has not been clarified yet. Here, we show the mechanism underlying IR‐induced BNP gene expression in H9c2 rat cardiomyocytes.IR induced expression of BNP mRNA and transactivation of BNP promoter in H9c2 cells. Activation of MAP kinase family members such as ERK1/2 and p38 MAPK was triggered by IR. U0126, an inhibitor of MEK, but not SB203580, an inhibitor of p38 MAPK, completely prevented increase of IR‐induced BNP gene expression. In addition, antioxidants such as DMSO and TEMPO diminished induction of BNP and phosphorylation of ERK1/2. To investigate whether increase in free intracellular calcium [Ca2+]i has a role in expression of BNP by IR, calcium chelator BAPTA‐AM was treated before reperfusion. BAPTA‐AM strongly reduced induction of BNP by IR. Moreover, calcium ionophore A23187 increased levels of BNP mRNA and phosphorylation of ERK1/2. Taken together, IR‐mediated BNP gene expression may be due to calcium‐ and ROS‐mediated activation of ERK1/2 in H9c2 cells. This research was supported by MRC from cell death disease research center funded by KOSEF.