Cyclic GMP–Dependent Protein Kinase Expression in Coronary Arterial Smooth Muscle in Response to Balloon Catheter Injury

Abstract

Abstract-Arterial smooth muscle cells undergo phenotypic and proliferative changes in response to balloon catheter injury. Nitric oxide (NO) and cGMP have been implicated in the inhibition of vascular smooth muscle cell proliferation and phenotypic modulation in cultured-cell studies. We have examined the expression of the major cGMP receptor protein in smooth muscle, cGMP-dependent protein kinase I (PKG), in response to balloon catheter injury in the swine coronary artery. On injury, there was a transient decrease in the expression of PKG in neointimal smooth muscle cells when compared with medial smooth muscle cells. The decrease in PKG expression was observed in the population of proliferating cells expressing the extracellular matrix protein osteopontin but not in cells present in the uninjured portion of the media. Coincident with the suppression of PKG expression in neointimal cells after injury, there was a marked increase in the expression of type II NO synthase (inducible NOS [iNOS], NOS-II) in the neointimal cells. These results suggest that PKG expression is transiently reduced in response to injury in the population of coronary arterial smooth muscle cells that are actively proliferating and producing extracellular matrix proteins. The reduction in PKG expression is also correlated temporally with increases in inflammatory activity in the injured vessels as assessed by iNOS expression. Coupled with our current knowledge regarding the role of PKG in the regulation of cultured cell phenotypes, these results imply that PKG may also regulate phenotypic modulation of vascular smooth muscle cells in vivo as well.

Vascular Smooth Muscle Cell Phenotype-Dependent Phosphodiesterase 4D Short Form Expression: Role of Differential Histone Acetylation on cAMP-Regulated Function

“…Serum starvation has been shown to modulate the phenotype of VSMCs from a synthetic/activated to a contractile/quiescent state (Li et al, 1999), a process known to involve chromatin remodeling, which adds credence to the notion that increased acetylation of CREs in the promoters of PDE4 genes can direct their transcription. It is interesting that the data presented here, in combination with our previous report demonstrating loss of PDE3A expression in rat synthetic/activated VSMCs (Dunkerley et al, 2002) and earlier reports of reduced soluble guanylyl cyclase and protein kinase G expression in synthetic/activated VSMCs (Anderson et al, 2000), may point to a more general phenotype-mediated reorganization of cyclic nucleotide signaling in these cells. Although provocative, the overall role that differential histone acetylation of the promoters controlling the expression of PDE3A, soluble guanylyl cyclase, and protein kinase G may play in these events remains to be assessed.…”

Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System

“…As discussed, repeated passaging might lead to downregulation of cGKI expression and/or alterations in other signaling components and proliferative responses. cGKI is expressed in SMCs of the media and neointima, although some studies 77,78 but not others 79 found a transient reduction of its expression after vascular injury. Adenoviral gene transfer of the constitutively active kinase domain of cGKI reduced neointima formation after vascular injury in rats and pigs, whereas gene transfer of wild-type cGKI␤ was ineffective.…”

Cyclic Guanosine Monophosphate-dependent Protein Kinase I Promotes Adhesion of Primary Vascular Smooth Muscle Cells

“…In addition to its potent vasorelaxant properties, it has been associated with vascular proliferative diseases, such as atherosclerosis and restenosis (von der Leyen et al, 1995;Janssens et al, 1998;Varenne et al, 1998;von der Thusen et al, 2004). Several studies (an excellent summary is given in Lincoln et al, 2006) suggested that activation of cGKI-dependent pathways has antimitogenic effects in smooth muscle cells (SMCs) in culture (Garg and Hassid, 1989;Boerth et al, 1997;Chiche et al, 1998;Brophy et al, 2002) and might be vasculoprotective in the intact animal (Anderson et al, 2000;Sinnaeve et al, 2002). Despite a large body of evidence that active cGKI acts antiproliferative, Hassid and coworkers reported that NO/ cGMP amplified the proliferative response of fibroblast growth factor-2 in primary VSMCs (Hassid et al, 1994).…”