title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Surgery, Duke University Medical Center, Durham, NC 27703, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Petrofski
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hata
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Williams
authors.forename: Cyrus J
authors.initials: CJ
authors.lastname: Parsa
authors.forename: Richard B
authors.initials: RB
authors.lastname: Thompson
authors.forename: Steven I
authors.initials: SI
authors.lastname: Hanish
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Gehrig
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Carmelo A
authors.initials: CA
authors.lastname: Milano
mesh_terms: D000818:Animals; D001026:Coronary Artery Bypass; D004285:Dogs; D015316:Genetic Therapy; D006965:Hyperplasia / Q000517:prevention & control; D010455:Peptides / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012501:Saphenous Vein / Q000473:pathology* / Q000637:transplantation*; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D010455:Peptides; D011994:Recombinant Proteins; C445259:beta-adrenergic receptor kinase inhibitory peptide