Rosuvastatin regulates vascular smooth muscle cell phenotypic modulation in vascular remodeling: role for the urokinase receptor.
The urokinase (uPA)/urokinase receptor (uPAR) multifunctional system is an important mediator of migration and proliferation of vascular smooth muscle cells (VSMC). However, whether uPA/uPAR-directed mechanisms are involved in the beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on vascular remodeling remains unexplored. In this study, we have investigated the effect of the hydrophilic statin rosuvastatin on neointimal remodeling, and the role of uPAR. Using an ex vivo organ and in vitro cell culture models we demonstrate that rosuvastatin decreases injury-induced neointima formation and proliferation of medial VSMC in porcine coronary arteries, as well as migration and proliferation of human coronary VSMC. Studies on the underlying mechanisms show that rosuvastatin impairs VSMC transition from their physiological contractile to the pathophysiological synthetic phenotype. These effects are mediated, at least in part, via uPAR, as confirmed by means of rosuvastatin-directed uPAR expression and uPAR silencing in both models. Our findings provide evidence that rosuvastatin modulates VSMC phenotypic changes and subsequently their proliferation and migration, and indicate the important role for uPAR in these processes. This mechanism contributes to the beneficial non-lipid lowering effect of rosuvastatin on negative vascular remodeling.
Kiyan
Julia
J
Hannover Medical School, Carl-Neuberg Strasse 1, Hannover D-30625, Germany.
Kusch
Angelika
A
Tkachuk
Sergey
S
Krämer
Jochen
J
Haller
Hermann
H
Dietz
Rainer
R
Smith
Graham
G
Dumler
Inna
I
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000293:injuries; D015536:Down-Regulation; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D034421:Sus scrofa; D017539:Tunica Intima / Q000187:drug effects; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C524898:PLAUR protein, human; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D014568:Urokinase-Type Plasminogen Activator