Abstract
BackgroundThe 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (also called statins) exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-β (TGF-β) in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies about the effect of statins on TGF-β/Smad pathway in atherosclerosis and vascular cells.MethodologyIn cultured vascular smooth muscle cells (VSMCs) statins enhanced Smad pathway activation caused by TGF-β. In addition, statins upregulated TGF-β receptor type II (TRII), and increased TGF-β synthesis and TGF-β/Smad-dependent actions. In this sense, statins, through Smad activation, render VSMCs more susceptible to TGF-β induced apoptosis and increased TGF-β-mediated ECM production. It is well documented that high doses of statins induce apoptosis in cultured VSMC in the presence of serum; however the precise mechanism of this effect remains to be elucidated. We have found that statins-induced apoptosis was mediated by TGF-β/Smad pathway. Finally, we have described that RhoA inhibition is a common intracellular mechanisms involved in statins effects. The in vivo relevance of these findings was assessed in an experimental model of atherosclerosis in apolipoprotein E deficient mice: Treatment with Atorvastatin increased Smad3 phosphorylation and TRII overexpression, associated to elevated ECM deposition in the VSMCs within atheroma plaques, while apoptosis was not detected.ConclusionsStatins enhance TGF-β/Smad pathway, regulating ligand levels, receptor, main signaling pathway and cellular responses of VSMC, including apoptosis and ECM accumulation. Our findings show that TGF-β/Smad pathway is essential for statins-dependent actions in VSMCs.
Highlights
The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, known as statins, have been largely reported as very useful drugs in atherosclerosis [1,2]
Our findings show that Transforming Growth Factor-b (TGF-b)/Smad pathway is essential for statins-dependent actions in vascular smooth muscle cells (VSMCs)
The present study investigates the mechanisms underlying the interaction between statins and TGF-b, and examines whether the beneficial effects of statins in atherosclerosis are attributable to a modulation of the TGF-b/Smad pathway by cholesterol independent mechanisms, through small GTP-ases inhibition
Summary
The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, known as statins, have been largely reported as very useful drugs in atherosclerosis [1,2]. They were initially used to treat atherosclerosis because their cholesterol-lowering effects. Transforming growth factor-b (TGF-b) is a pleiotropic cytokine involved in many human diseases, including cardiovascular disease. The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors ( called statins) exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-b (TGF-b) in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. There are no studies about the effect of statins on TGF-b/Smad pathway in atherosclerosis and vascular cells
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