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(Circulation Research. 2001;88:103.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Soluble Guanylate Cyclase ₁ and ß₁ Gene Transfer Increases NO Responsiveness and Reduces Neointima Formation After Balloon Injury in Rats via Antiproliferative and Antimigratory Effects

Peter Sinnaeve, Jean-Daniel Chiche, Zengxuang Nong, Olivier Varenne, Natascha Van Pelt, Hilde Gillijns, Desire Collen, Kenneth D. Bloch, Stefan Janssens

From the Center for Transgene Technology and Gene Therapy (P.S., Z.N., O.V., H.G., D.C., S.J.), Flanders Interuniversity Institute for Biotechnology, and the Cardiac Unit (P.S., N.V.P., S.J.), University Hospital Gasthuisberg, University of Leuven, Belgium, and Cardiovascular Research Center and Cardiology Division, Department of Medicine (J-D.C., K.D.B.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Stefan Janssens, MD, PhD, Cardiac Unit and Center for Transgene Technology and Gene Therapy, KU-Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium. E-mail stefan.janssens{at}med.kuleuven.ac.be

Abstract—In vascular smooth muscle cells, NO stimulates the synthesis of cGMP by soluble guanylate cyclase (sGC), a heterodimer composed of ₁ and ß₁ subunits. NO/cGMP signal transduction affects multiple cell functions that contribute to neointima formation after vascular injury. Balloon-induced vascular injury was found to decrease sGC subunit expression and enzyme activity in rat carotid arteries. The effect of restoring sGC enzyme activity on neointima formation was investigated using recombinant adenoviruses specifying sGC ₁ and ß₁ subunits (Ad1 and Adß1). Coinfection of cultured rat aortic smooth muscle cells with Ad1 and Adß1 increased NO-stimulated intracellular cGMP levels 60-fold and decreased DNA synthesis and migration by 16% and 48%, respectively. Immunoreactivity for ₁ and ß₁ subunits colocalized in carotid arteries infected with Ad1 and Adß1. Molsidomine-stimulated carotid tissue cGMP levels were greater after coinfection with Ad1 and Adß1 than after infection with a control virus, AdRR5 (0.53±0.09 pmol/mg protein, mean±SEM, versus 0.23±0.09, P<0.05). Mean intima/media ratio, 2 weeks after balloon injury and twice-daily administration of 5 mg/kg molsidomine, was less in rats coinfected with Ad1 and Adß1 than in rats infected with AdRR5 or in uninfected rats (0.36±0.11 versus 0.81±0.13 and 0.75±0.25, respectively, P<0.05). Thus, Ad1 and Adß1 gene transfer to balloon-injured rat carotid arteries increases NO responsiveness and attenuates neointima formation via a direct antiproliferative and antimigratory effect on vascular smooth muscle cells.

Key Words: cyclic GMP • soluble guanylate cyclase • nitric oxide • adenovirus • gene therapy

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