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(Circulation. 2002;105:2911.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Overexpression of a Constitutively Active Protein Kinase G Mutant Reduces Neointima Formation and In-Stent Restenosis

Peter Sinnaeve, MD, PhD; Jean-Daniel Chiche, MD; Hilde Gillijns; Natascha Van Pelt; Douglas Wirthlin, MD; Frans Van de Werf, MD, PhD; Desire Collen, MD, PhD; Kenneth D. Bloch, MD; Stefan Janssens, MD, PhD

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

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

Background— Neointima formation after arterial injury is associated with reduced vascular cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), a major cGMP effector in vascular smooth muscle. We tested the effect of PKG overexpression on the neointimal response to vascular injury.

Methods and Results— Infection of cultured rat aortic smooth muscle cells (RASMCs) with an adenoviral vector specifying a cGMP-independent, constitutively active PKG mutant (AdPKGcat) reduced serum-induced migration by 33% and increased serum-deprivation–induced apoptosis 2-fold (P<0.05 for both). Infection with wild-type PKG (AdPKG), in the absence of cGMP, did not affect migration or apoptosis. Two weeks after balloon-injured rat carotid arteries were infected with 1x 10¹⁰ pfu AdPKGcat (n=12), AdPKG (n=8), or a control adenovirus (n=8), intima-to-media ratio was less in AdPKGcat-infected arteries than in AdPKG- or control adenovirus–infected vessels (0.26±0.06 versus 0.61±0.12 and 0.70±0.12, respectively, P<0.05 for both). Two weeks after intramural administration of 1.75x10¹⁰ pfu AdPKGcat (n=8) or a control adenovirus (n=8) into porcine coronary arteries with in-stent restenosis, luminal diameter was greater in AdPKGcat-infected arteries than in control adenovirus-infected vessels (2.32±0.16 versus 1.81±0.13 mm, P=0.028), associated with reduced neointimal area (3.30±0.24 versus 4.15±0.13 mm², P=0.008), neointima-to-vessel area ratio (0.42±0.05 versus 0.58±0.04, P<0.05), and percent stenosis (45±6% versus 70±4%, P<0.05).

Conclusions— Expression of a constitutively active PKG reduces neointima formation after balloon injury in rats and reduces coronary in-stent restenosis in pigs. PKGcat gene transfer may be a promising strategy for vasculoproliferative disorders.

Key Words: kinases • nitric oxide • apoptosis • restenosis

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