A G_βγ inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts

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 βγ subunits of heterotrimeric G proteins (G_βγ) and downstream effectors such as mitogen-activated protein kinases. A peptide consisting of the carboxyl-terminus of the β-adrenergic receptor kinase (βARKct) binds G_βγ, thereby inhibiting G_βγ signaling. Utilizing a recombinant adenovirus containing the coding sequence for the βARKct peptide (AdβARKct), this study investigates whether treatment of the vein graft with AdβARKct 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 AdβARKct (n = 8). A subset of dogs (n = 3) were sacrificed on postoperative day 7 and βARKct expression confirmed by Northern blotting. Results: Arteriograms performed on postoperative day 90 confirmed that saphenous vein grafts were patent. At postoperative day 90, AdβARKct-treated grafts demonstrated reduced intimal area compared to empty virus and saline treated animals (P < .05). Additionally, AdβARKct 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 βARKct expression in aortocoronary saphenous vein grafts reduces intimal hyperplasia and decreases vascular smooth muscle cell proliferation in vitro via inhibition of G_βγ- mediated mitogen-activated protein kinase activation. Modulation of G _βγ via βARKct may represent a novel therapy to reduce intimal hyperplasia and saphenous vein graft failure.