3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Attenuate Vascular Smooth Muscle Proliferation by Preventing Rho GTPase-induced Down-regulation of p27

Abstract

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 M), 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 p27Kip1 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 p27Kip1 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 p27Kip1 and inhibited retinoblastoma hyperphosphorylation. In contrast, activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreased p27Kip1 and increased SMC DNA synthesis. These findings indicate that the down-regulation of p27Kip1 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.

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

“…5). The antiproliferative effects of simvastatin, previously reported against a wide variety of tumor cells (6,7,14,15), could be due to downregulation of these gene products. We also found for the first time that expression of cyclin D1 and COX-2 was down-modulated by simvastatin.…”

“…Beside cholesterol-lowering activity, there is increasing evidence that statins have potential in a wide variety of diseases, including cancer (5-7). Statins have also been shown to promote bone formation (8), modulate immune system (9), suppress inflammation (10), modulate angiogenesis (11,12), and inhibit the proliferation of wide variety of cells (5)(6)(7)(13)(14)(15).…”

“…Statins have been shown to bind lymphocyte function-associated Ag-1 (16), inhibit geranylgeranylation of protein (17), regulate cyclin-dependent kinase inhibitors p21 (18) and p27 (14), and interfere with the Raf/mitogen-activated protein extracellular kinase/extracellular signal-regulated protein kinase pathway (15). The use of lovastatin in the synchronization of cells at the G 1 phase of the cell cycle has been well described (19).…”

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

“…2,6,7 Statins have shown beneficial effects on hepatic fibrosis and portal hypertension in cirrhosis, most likely because the inhibition of HMG-CoA-reductase impedes small GTPases (RhoA and Ras). [8][9][10][11][12][13] The portal pressure-lowering effect was attributed to the inhibition of RhoA translocation to the membrane of myofibroblastic HSC and thereby disruption of RhoA/Rho-kinase signaling, resulting in decreased contraction of these cells and reduced intrahepatic resistance. 9 In a model of progressive biliary fibrosis using bile duct ligation (BDL) in rats, 14 prophylactic and early atorvastatin treatment attenuated activation of MFB and subsequent collagen deposition.…”

Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells

“…Several components of Rho GTPase signaling are available for pharmacological manipulation, including HMG-CoA reductase, GGTases, FTase, or the downstream effector Rho-associated kinase (ROCK), to examine Rho signaling mechanisms and function (18,26,31,35). Focusing on NO, recent work has demonstrated that inhibition of Rho GTPase activity with mevastatin, an HMG-CoA reductase inhibitor, in vascular smooth muscle cells increases NOS2 expression, implying that Rho activation may decrease NOS2 expression (23).…”