New targets for PPARgamma in the vessel wall: implications for restenosis.

Peroxisome proliferator-activated receptor {gamma} (PPARgamma), the nuclear receptor that binds the insulin-sensitizing thiazolidinediones (TZDs), is prominently upregulated in intimal vascular smooth muscle cells (VSMC) after mechanical injury to the vessel wall. Several TZD PPARgamma ligands have been shown to inhibit neointima formation in both normal and insulin-resistant vasculature. The suppression of intimal hyperplasia by TZD PPARgamma ligands probably results from their activity to inhibit VSMC growth and promote apoptosis. TZDs prevent VSMC proliferation by blocking the activity of regulatory proteins, such as phosphorylation of the retinoblastoma protein (Rb). Rb functions as a G(1) gatekeeper by controlling S phase gene expression mediated by the E2F transcription factor. Consistent with their effect on Rb phosphorylation, PPARgamma ligands inhibit the mitogenic induction of minichromosome maintenance (MCM) proteins 6 and 7, two E2F-regulated S phase genes essential for DNA replication. PPARgamma ligands also induced apoptosis in VSMC, which correlated with a potent induction of GADD45, a gene implicated in controlling cell growth and survival. A constitutively active form of PPARgamma targeted the same cell cycle regulators as did PPARgamma ligands, consistent with a nuclear-receptor-dependent mechanism of action. This review will summarize mechanisms through which PPARgamma modulates VSMC proliferation and apoptosis suggesting that PPARgamma itself is a novel important regulator of cell cycle and apoptosis and may provide a new therapeutic approach to prevent restenosis.

TNFalpha inhibits insulin's antiapoptotic signaling in vascular smooth muscle cells.

Tumor necrosis factor alpha (TNFalpha) interferes with insulin signaling in adipose tissue and may promote insulin resistance. Insulin resistance is associated with vascular injury, but little is known about the interaction of TNFalpha and insulin in the vasculature. By activating the Insulin receptor (IR) --> IRS-1 --> phosphatidylinositol-3-kinase (PI3K) --> Akt-pathway, insulin protects vascular smooth muscle cells (VSMC) from undergoing apoptosis. We therefore investigated the effect of TNFalpha on insulin's antiapoptotic signaling in rat aortic VSMC. Insulin induced rapid tyrosine-phosphorylation of the IR and IRS-1 and caused a 2.8-fold increase of IRS-1-bound PI3K. TNFalpha had no effect on insulin-induced tyrosine-phosphorylation of IR or IRS-1, but inhibited insulin-stimulated IRS-1/PI3K-association by 84%. Insulin-induced phosphorylation of Akt downstream of PI3K was inhibited by TNFalpha in a similar pattern. We next examined the effect of TNFalpha on insulin's protective actions on H(2)O(2)-induced apoptosis. Insulin alone prevented 72.8% of H(2)O(2)-induced apoptosis, which was significantly inhibited by TNFalpha. TNFalpha alone did not induce apoptosis. In contrast, TNFalpha had no effect on PDGF-induced antiapoptotic signal transduction via Akt. Thus, TNFalpha selectively interferes with insulin's antiapoptotic signaling in VSMC by inhibiting the association of IRS-1/PI3K and the downstream activation of Akt.

Expression of CD40 in vascular smooth muscle cells and macrophages is associated with early development of human atherosclerotic lesions.

CD40-CD154-mediated signaling has recently been described as playing a role in cellular functions involved in atherosclerotic processes. CD40 is expressed in macrophages, lymphocytes, endothelial cells, and vascular smooth muscle cells. However, cross-sectional studies investigating the expression of CD40 in atherosclerotic lesions are lacking. In the present study the expression of CD40 was studied in atherosclerotic lesions from 43 patients classified according to the World Health Organization criteria. Serial immunohistologic stainings of human iliac arteries from 43 patients were performed using monoclonal antibodies. Lesions were classified according to World Health Organization criteria, and CD40 expression was analyzed with regard to cell morphology and cellular markers by 2 independent observers. Human atherosclerotic lesions revealed a significant increase in intimal thickness, number of inflammatory infiltrates, and CD40-positive macrophages and vascular smooth muscle cells with progression of the lesions. This increase was most prominent from stage 0 to stage I. A significant correlation between intimal thickness and CD40-positive macrophages (r = 0.75, p <0.0005) and CD40-positive vascular smooth muscle cells (r = 0.81, p <0.0005) was observed. Ligation of the cellular CD40 receptor contributes to inflammatory cellular events in human vascular smooth muscle cells. These data suggest a direct association of CD40 expression in atherosclerotic lesions with early plaque development.