A Gbetagamma inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

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 betagamma subunits of heterotrimeric G proteins (G(betagamma)) and downstream effectors such as mitogen-activated protein kinases. A peptide consisting of the carboxyl-terminus of the beta-adrenergic receptor kinase (betaARKct) binds G(betagamma), thereby inhibiting G(betagamma) signaling. Utilizing a recombinant adenovirus containing the coding sequence for the betaARKct peptide (AdbetaARKct), this study investigates whether treatment of the vein graft with AdbetaARKct 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 AdbetaARKct (n = 8). A subset of dogs (n = 3) were sacrificed on postoperative day 7 and betaARKct expression confirmed by Northern blotting.

RESULTS:

Arteriograms performed on postoperative day 90 confirmed that saphenous vein grafts were patent. At postoperative day 90, AdbetaARKct-treated grafts demonstrated reduced intimal area compared to empty virus and saline treated animals (P < .05). Additionally, AdbetaARKct 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 betaARKct expression in aortocoronary saphenous vein grafts reduces intimal hyperplasia and decreases vascular smooth muscle cell proliferation in vitro via inhibition of G(betagamma)-mediated mitogen-activated protein kinase activation. Modulation of G(betagamma) via betaARKct may represent a novel therapy to reduce intimal hyperplasia and saphenous vein graft failure.

• Authors: 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
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 130 Issue 6 Pg. 1683-90 (Dec 2005) ISSN: 1097-685X [Electronic] United States
• PMID: 16308016 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Peptides
• Recombinant Proteins
• beta-adrenergic receptor kinase inhibitory peptide

Topics

• Animals
• Coronary Artery Bypass
• Dogs
• Genetic Therapy
• Hyperplasia (prevention & control)
• Peptides (therapeutic use)
• Recombinant Proteins (therapeutic use)
• Saphenous Vein (pathology, transplantation)
• Tunica Intima (pathology)