Statins regulate alpha2beta1-integrin expression and collagen I-dependent functions in human vascular smooth muscle cells.
HMG-CoA reductase inhibitors have direct vascular effects that contribute to plaque stability. In the current study, the authors demonstrate that the HMG-CoA reductase inhibitors atorvastatin and pravastatin augment the adhesion of human (HSMCs) and rat aortic smooth muscle cells (RASMCs) to collagen I via induction of alpha2beta1-integrin receptors. Atorvastatin (0.1 microM ) increased the adhesion of HSMCs to collagen I up to 2-fold (p < 0.01) and pravastatin (1.0 microM ) up to 1.8-fold (p < 0.01) after treatment of at least 24 h. This increase in adhesion was concentration dependent and was observed for treatment periods from 16 to 72 h. Inhibition of isoprenoid synthesis with mevalonate and geranyl-geraniol prevented the statin-induced effect on human and rat smooth muscle cells. Flow cytometry revealed an increased expression of alpha2- and beta1-integrins after treatment with atorvastatin (0.1 microM ) at 24 and 48 h. Atorvastatin increased levels of beta1-integrin mRNA after 12- and 24-h treatment in HSMCs, which was inhibited by mevalonate. Furthermore, atorvastatin (0.1 microM ) and pravastatin (1.0 microM ) inhibited chemotaxis of HSMCs on collagen I, which was also reversed by mevalonate treatment. In contrast, inhibition of beta1-integrins with a specific antibody nearly doubled (p < 0.01) the rate of chemotaxis. These data indicate that the chemotactic activity in HSMCs is inhibited in part by up-regulation of alpha2beta1-integrin receptors. The current study indicates that HMG-CoA reductase inhibitors increase cell-matrix interaction with collagen I via induction of alpha2beta1-integrins and increased adhesion to collagen I.
Graf
Kristof
K
Deutsches Herzzentrum Berlin, Department of Medicine/Cardiology, Berlin, Germany. graf@dhzb.de
Kappert
Kai
K
Stawowy
Philipp
P
Bokemeyer
Johanna
J
Blaschke
Florian
F
Schmidt
Gunther
G
Kintscher
Ulrich
U
Goetze
Stephan
S
Fleck
Eckart
E
D000818:Animals; D000069059:Atorvastatin; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D024042:Collagen Type I / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D038982:Integrin alpha2beta1 / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D017035:Pravastatin / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D024042:Collagen Type I; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D038982:Integrin alpha2beta1; D011758:Pyrroles; D000069059:Atorvastatin; D017035:Pravastatin