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J Thorac Cardiovasc Surg 2005;130:1683-1690
© 2005 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

A G_ß inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts

^a Surgery
^b Medicine, Duke University Medical Center, Durham, NC
^c Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pa

Received for publication August 22, 2004; revisions received December 12, 2004; accepted for publication January 10, 2005.

^_* Address for reprints: Carmelo A. Milano, MD, Box 3043, Department of Surgery, Duke University Medical Center, Durham, NC 27703 (Email: milan002{at}mc.duke.edu).

OBJECTIVE: Approximately 50% of aortocoronary saphenous vein grafts are occluded 10 years after coronary revascularization surgery. Intimal hyperplasia, a critical component in saphenous vein graft failure, is defined by vascular smooth muscle cell proliferation, which is mediated in part by ß subunits of heterotrimeric G proteins (G_ß) and downstream effectors such as mitogen-activated protein kinases. A peptide consisting of the carboxyl-terminus of the ß-adrenergic receptor kinase (ßARKct) binds G_ß, thereby inhibiting G_ß signaling. Utilizing a recombinant adenovirus containing the coding sequence for the ßARKct peptide (AdßARKct), this study investigates whether treatment of the vein graft with AdßARKct reduces intimal hyperplasia in a large animal model of aortocoronary saphenous vein graft intimal hyperplasia.

METHODS: Twenty-seven dogs (27-32 kg) underwent aortocoronary bypass grafting to the left anterior descending artery using autologous saphenous vein. Vein grafts were treated with saline (n = 8), an empty adenovirus (n = 8), or AdßARKct (n = 8). A subset of dogs (n = 3) were sacrificed on postoperative day 7 and ßARKct expression confirmed by Northern blotting.

RESULTS: Arteriograms performed on postoperative day 90 confirmed that saphenous vein grafts were patent. At postoperative day 90, AdßARKct-treated grafts demonstrated reduced intimal area compared to empty virus and saline treated animals (P < .05). Additionally, AdßARKct treatment of isolated vascular smooth muscle cells in vitro inhibited mitogen-activated protein kinase activation and decreased overall vascular smooth muscle cell proliferation.

CONCLUSION: This study demonstrates that ßARKct expression in aortocoronary saphenous vein grafts reduces intimal hyperplasia and decreases vascular smooth muscle cell proliferation in vitro via inhibition of G_ß-mediated mitogen-activated protein kinase activation. Modulation of G_ß via ßARKct may represent a novel therapy to reduce intimal hyperplasia and saphenous vein graft failure.

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