Regulation of smooth muscle specific gene expression by PKG and mechanisms regulating PKG expression in smooth muscle cells

Cyclic GMP-dependent protein kinase I (PKG) is highly expressed in smooth muscle cells (SMC) and mediates the effects of nitric oxide (NO) on smooth muscle relaxation and SMC-specific gene expression. To understand the mechanisms by which PKG stimulates SMC-specific gene expression, we examined the effects of PKG over-expression in passaged rat aortic SMC that express low levels of PKG and SMC-specific genes. PKG enhances serumresponse factor (SRF) and myocardin (MY)induced reporter gene expression in SMC. These effects were not dependent on induction of either SRF or MY. The Ternary Complex Element transcription factor, Elk-1, is known to inhibit SRF-MY induced SMC gene expression when phosphorylated in response to platelet derived growth factor (PDGF). PKG inhibited Elk-1 repression of SRF-MY gene transcription by stimulating post-translational modification of phospho-Elk-1 via the small ubiquitin-like modifier (SUMO). The mechanism of PKG-induced sumoylation of Elk-1 may be dependent on the phosphorylation of SENP-1 (sumo-specific protease 1) at ser-125. These results suggest that PKG regulates SRF-MY gene expression through de-repression of Elk-1 on SMC-specific promoters.