[Aortic trauma].

The mechanism by which platelet-derived growth factor (PDGF) regulates vascular smooth muscle cell (SMC) DNA synthesis is unknown, but may involve isoprenoid intermediates of the cholesterol biosynthetic pathway. Inhibition of isoprenoid synthesis with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, simvastatin (Sim, 1-10 microM), inhibited PDGF-induced SMC DNA synthesis by >95%, retinoblastoma gene product hyperphosphorylation by 90%, and cyclin-dependent kinases (cdk)-2, -4, and -6 activity by 80 +/- 5, 50 +/- 3, and 48 +/- 3%, respectively. This correlated with a 20-fold increase in p27(Kip1) without changes in p16, p21(Waf1), or p53 levels compared with PDGF alone. Since Ras and Rho require isoprenoid modification for membrane localization and are implicated in cell cycle regulation, we investigated the effects of Sim on Ras and Rho. Up-regulation of p27(Kip1) and inhibition of Rho but not Ras membrane translocation by Sim were reversed by geranylgeranylpyrophosphate, but not farnesylpyrophosphate. Indeed, inhibition of Rho by Clostridium botulinum C3 transferase or overexpression of dominant-negative N19RhoA mutant increased p27(Kip1) and inhibited retinoblastoma hyperphosphorylation. In contrast, activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreased p27(Kip1) and increased SMC DNA synthesis. These findings indicate that the down-regulation of p27(Kip1) by Rho GTPase mediates PDGF-induced SMC DNA synthesis and suggest a novel direct effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors on the vascular wall.

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PubMed1999

Release of soluble ICAM-1 from human lung fibroblasts, aortic smooth muscle cells, dermal microvascular endothelial cells, bronchial epithelial cells, and keratinocytes.

We determined effects of IL-1alpha, TNFalpha and IFNgamma on sICAM-1 release in culture media from human aortic smooth muscle cells (AOSMC), dermal microvascular endothelial cells (DMEC), keratinocytes (KC), bronchial epithelial cells (BEC) and lung fibroblasts (LF) as determined by ELISA. Under basal conditions of cultures for 20 h, low concentrations of sICAM-1 were only detected in the culture media of two (DMEC and BEC) of these cell types. IL-1alpha, TNFalpha and IFNgamma stimulated sICAM-1 from these cells. IFNgamma stimulated more shedding from AOSMC, BEC and KC than IL-1alpha or TNFalpha. TNFalpha enhanced more sICAM-1 release from DEMC than from AOSMC, BEC and LF. IL-1alpha and IFNgamma or TNFalpha and IFNgamma acted synergistically to enhance shedding of sICAM-1 from these cells. The levels sICAM-1 in pathophysiological conditions may influence leukocyte-vascular cell interactions to block leukocyte transmigration to tissue injury sites as a negative feedback mechanism.

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