on October 29, 2009
Published online before print October 29, 2009, doi: 10.1161/ATVBAHA.109.197822
Submitted on September 22, 2009
Accepted on October 15, 2009
HO-1 and CO Decrease Platelet-Derived Growth Factor-Induced Vascular Smooth Muscle Cell Migration Via Inhibition of Nox1
Andres I. Rodriguez ;
From Department of Surgery (A.I.R., A.G., B.S.Z., P.M.B.), Department of Anesthesiology (E.E.K.), Department of Pharmacology and Chemical Biology (P.J.P., P.M.B.), and Vascular Medicine Institute (E.E.K., P.J.P., B.S.Z., P.M.B.), University of Pittsburgh School of Medicine, Pittsburgh, Pa.
* To whom correspondence should be addressed. E-mail: bauerpm{at}upmc.edu.
Objective—Heme oxygenase-1 (HO-1), via its enzymatic degradation products, exhibits cell and tissue protective effects in models of vascular injury and disease. The migration of vascular smooth muscle cells (VSMC) from the medial to the intimal layer of blood vessels plays an integral role in the development of a neointima in these models. Despite this, there are no studies addressing the effect of increased HO-1 expression on VSMC migration.
Results and Methods—The effects of increased HO-1 expression, as well as biliverdin, bilirubin, and carbon monoxide (CO), were studied in in vitro models of VSMC migration. Induction of HO-1 or CO, but not biliverdin or bilirubin, inhibited VSMC migration. This effect was mediated by the inhibition of Nox1 as determined by a range of approaches, including detection of intracellular superoxide, nicotinamide adenine dinucleotide phosphate oxidase activity measurements, and siRNA experiments. Furthermore, CO decreased platelet-derived growth factor-stimulated, redox-sensitive signaling pathways.
Conclusion—Herein, we demonstrate that increased HO-1 expression and CO decreases platelet-derived growth factor-stimulated VSMC migration via inhibition of Nox1 enzymatic activity. These studies reveal a novel mechanism by which HO-1 and CO may mediate their beneficial effects in arterial inflammation and injury.
Key words: carbon monoxide • heme oxygenase-1 • NADPH oxidase • Nox1 • vascular smooth muscle