TY - JOUR
T1 - A Gβγ inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts
AU - Petrofski, Jason A.
AU - Hata, Jonathan A.
AU - Williams, Matthew L.
AU - Parsa, Cyrus J.
AU - Thompson, Richard B.
AU - Hanish, Steven I.
AU - Gehrig, Thomas R.
AU - Koch, Walter J.
AU - Milano, Carmelo A.
N1 - Funding Information:
This work was supported in part by National Institutes of Health grants HL65360 (W.J.K.) and HL072183-01Al (C.A.M.) and by National Research Service Award grants 5F32-HL-68437-02 (J.A.P.) and 5F32H71387-2 (J.A.H.).
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jtcvs.2005.01.024
DO - 10.1016/j.jtcvs.2005.01.024
M3 - Article
C2 - 16308016
AN - SCOPUS:27944445992
SN - 0022-5223
VL - 130
SP - 1683
EP - 1690
JO - Journal of Thoracic and Cardiovascular Surgery
JF - Journal of Thoracic and Cardiovascular Surgery
IS - 6
ER -