PKA promotes MEF2/HDAC repression of the c‐Jun promoter in vascular smooth muscle cells

Abstract

Vascular smooth muscle cells (VSMCs) do not terminally differentiate, but can modulate their phenotype in response to extracellular stimuli. Although proliferative VSMCs are required during vascular repair, the activated phenotype also plays a role in vascular disease. To investigate the role of myocyte enhancer factor 2 (MEF2) in the induction of the growth-responsive gene, c-Jun, we utilized the A10 line. Mitogenic stimulation by platelet derived growth factor (PDGF) resulted in marked induction of c-Jun protein and promoter activity. This induction was attenuated by rottlerin and KN-62. Given that these signaling pathways have been shown to relieve the repressive effects of histone deacetylases (HDACs) on MEF2 proteins, we overexpressed HDAC4, which repressed the c-Jun promoter. Mutation of the MEF2 binding site in the c-Jun promoter resulted in activation during quiescent conditions, while treatment with trichostatin A, increased c-Jun protein. Interestingly, activation of protein kinase A (PKA) prevented PDGF induction of c-Jun, and repressed a MEF2-dependent reporter gene. PKA also caused nuclear accumulation of HDAC4 and stabilized the interaction of HDAC4 with MEF2D. Thus, it appears that MEF2 and HDAC4 act to repress c-Jun expression in quiescent VSMCs, PKA enhances this repression, and PDGF derepresses through CaMKs and novel PKCs. Supported by CIHR and the Heart and Stroke Foundation of Canada.