Abstract
Platelet-derived growth factor (PDGF) inhibits expression of smooth muscle (SM) genes in vascular smooth muscle cells and blocks induction by arginine vasopressin (AVP). We have previously demonstrated that suppression of SM-alpha-actin by PDGF-BB is mediated in part through a Ras-dependent pathway. This study examined the role of phosphatidylinositol 3-kinase (PI3K)y and its downstream effector, Akt, in regulating SM gene expression. PDGF caused a rapid sustained activation of Akt, whereas AVP caused only a small transient increase. PDGF selectively caused a sustained stimulation of p85/p110 alpha PI3K. In contrast, p85/110 beta PI3K activity was not altered by either PDGF or AVP, whereas both agents caused a delayed activation of Class IB p101/110 gamma PI3K. Expression of a gain-of-function PI3K or myristoylated Akt (myr-Akt) mimicked the inhibitory effect of PDGF on SM-alpha-actin and SM22 alpha expression. Pretreatment with LY 294002 reversed the inhibitory effect of PDGF. Expression of myr-Akt selectively inhibited AVP-induced activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinases, which we have shown are critical for induction of these genes. Nuclear extracts from PDGF-stimulated or myr-Akt expressing cells showed reduced serum response factor binding to SM-specific CArG elements. This was associated with appearance of serum response factor in the cytoplasm. These data indicate that activation of p85/p110 alpha/Akt mediates suppression of SM gene expression by PDGF.
Highlights
Phenotypic modulation of vascular smooth muscle cells (VSMC)1 is critical during development and in the onset of diseases such as atherosclerosis and hypertension
Platelet-derived growth factor (PDGF) gave a sustained increase in Akt activity ϳ10-fold, whereas a more transient and modest increase was seen with arginine vasopressin (AVP) stimulation (Fig. 1B)
VSMC differentiation is important during vascular development, and alterations in VSMC phenotype play a major role in the progression of cardiovascular diseases including atherosclerosis, hypertension, and restenosis [2, 30, 31], all of which are diseases of mature vessels
Summary
Phenotypic modulation of vascular smooth muscle cells (VSMC) is critical during development and in the onset of diseases such as atherosclerosis and hypertension. The proximal region of the rat SM-␣-actin promoter contains two CArG elements, which are critical for regulation of promoter activity by vasoconstrictor hormones and growth factors [8, 9]. In VSMC, platelet-derived growth factor (PDGF) mediates a variety of biological effects through activation of intracellular signal transduction pathways including the MAP kinase cascade, phosphatidylinositol turnover, and calcium mobilization. These effects contribute to smooth muscle cell proliferation and directed migration [13]. Suppression of SM-␣-actin appeared to be mediated through a Ras-dependent/Raf-independent pathway involving effector pathways that are not well characterized
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