IKCa1 is an immediate early response gene mediating coronary smooth muscle phenotypic modulation

Abstract

We previously demonstrated functional upregulation of intermediate-conductance Ca2+-activated K+ channel (IKCa1) with the development of early coronary atherosclerosis in vivo and as a prerequisite for platelet-derived growth factor BB (PDGF-BB) induced porcine coronary smooth muscle cell (CSMC) dedifferentiation and migration in vitro. Our objective was to examine the temporal regulation of IKCa1 and smooth muscle marker gene expression in porcine CSMC exposed to coronary balloon injury (CBI) in vivo or PDGF-BB in vitro. Two hours following CBI, laser capture microdissection of media from injured vessels demonstrated higher IKCa1, c-jun, and c-fos, but unaltered amounts of SMMHC mRNA compared to control media. PDGF-BB increased enrichment of H4 acetylation and c-jun to the AP-1 binding site of the IKCa1 promoter ~4-fold, an effect blocked by TRAM-34, a specific IKCa1 channel blocker. PDGF-BB increased IKCa1 and decreased myocardin mRNA at 30 minutes, but did not decrease smooth muscle myosin heavy chain (SMMHC) or smoothelin expression until 10 hours. In conclusion, these data indicate that AP-1 dependent upregulation of IKCa1 is an immediate and requisite factor initiating smooth muscle specific gene suppression, i.e. CSMC phenotypic modulation, during coronary injury. Supported by: NIH HL52490