A Gβγ inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts

Jason A. Petrofski, Jonathan A. Hata, Matthew L. Williams, Cyrus J. Parsa, Richard B. Thompson, Steven I. Hanish, Thomas R. Gehrig, Walter J. Koch, Carmelo A. Milano

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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 (Gβγ) and downstream effectors such as mitogen-activated protein kinases. A peptide consisting of the carboxyl-terminus of the β-adrenergic receptor kinase (βARKct) binds Gβγ, thereby inhibiting Gβγ 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 Gβγ- 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.

Original languageEnglish (US)
Pages (from-to)1683-1690
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume130
Issue number6
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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