title: Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.
abstract: BACKGROUND
  The 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-beta (TGF-beta) in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies about the effect of statins on TGF-beta/Smad pathway in atherosclerosis and vascular cells.
  
  
  METHODS
  In cultured vascular smooth muscle cells (VSMCs) statins enhanced Smad pathway activation caused by TGF-beta. In addition, statins upregulated TGF-beta receptor type II (TRII), and increased TGF-beta synthesis and TGF-beta/Smad-dependent actions. In this sense, statins, through Smad activation, render VSMCs more susceptible to TGF-beta induced apoptosis and increased TGF-beta-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-beta/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.
  
  
  CONCLUSIONS
  Statins enhance TGF-beta/Smad pathway, regulating ligand levels, receptor, main signaling pathway and cellular responses of VSMC, including apoptosis and ECM accumulation. Our findings show that TGF-beta/Smad pathway is essential for statins-dependent actions in VSMCs.
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Rodríguez-Vita
authors.forename: Eva
authors.initials: E
authors.lastname: Sánchez-Galán
authors.forename: Beatriz
authors.initials: B
authors.lastname: Santamaría
authors.forename: Elsa
authors.initials: E
authors.lastname: Sánchez-López
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodrigues-Díez
authors.forename: Luís Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000473:pathology / Q000517:prevention & control; D000069059:Atorvastatin; D002478:Cells, Cultured; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D054460:rho-Associated Kinases / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000502:physiology
chemical_list: D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000069059:Atorvastatin; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein