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(Circulation. 2005;111:1833-1840.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Local Gene Transduction of Cyclooxygenase-1 Increases Blood Flow in Injured Atherosclerotic Rabbit Arteries

Qi Liu, PhD; Zhi-Qiang Chen, MD; George C. Bobustuc, MD; Janice M. McNatt, PhD; Harry Segall, MD, PhD; Su Pan, MD, PhD; James T. Willerson, MD; Pierre Zoldhelyi, MD

From the Wafic Said Molecular Cardiology and Gene Therapy Research Laboratory, Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston (Q.L., Z.Q.C., G.C.B., H.S., S.P., J.T.W., P.Z.), and the Department of Medicine (Cardiology), The University of Texas-Houston Medical School (Z.Q.C., J.M.M., J.T.W., P.Z.).

Correspondence to Pierre Zoldhelyi, MD, Texas Heart Institute, 6770 Bertner Ave, MC 2-255, Houston, TX 77225-0345. E-mail zoldhely{at}airmail.net

Received April 19, 2004; revision received November 2, 2004; accepted November 23, 2004.

Background— Cyclooxygenase-1 (COX-1) is the rate-limiting component in the synthesis of prostacyclin (PGI₂), an important vasodilator and antithrombotic molecule. In balloon-injured, atherosclerosis-free porcine arteries, COX-1 gene transduction increases PGI₂ production, induces durable vasodilation, and reduces thrombus formation. We tested the effectiveness of COX-1 local gene transduction for the prevention of postangioplasty restenosis in atherosclerotic arteries in a hypercholesterolemic rabbit model.

Methods and Results— We injured 1 carotid artery in 43 Watanabe heritable hyperlipidemic rabbits and performed local gene transduction using a viral vector containing the COX-1 gene (AdCOX-1, n=22) or no genes (Adnull, n=21). Three days later, AdCOX-1–treated arteries stimulated with arachidonic acid produced 100% more PGI₂ (P<0.01), 400% more prostaglandin E₂ (PGE₂) (P<0.01), 400% more prostaglandin E₁ (PGE₁) (P<0.01), and 250% more cAMP (P<0.05) than Adnull-treated arteries. Twenty-eight days after treatment, Doppler sonography showed that blood flow velocity was preserved in AdCOX-1–treated arteries (ratio 0.92, injured compared with contralateral uninjured carotid artery) but reduced in Adnull-treated arteries (ratio 0.39), suggesting that AdCOX-1 prevented restenosis after injury. COX-1–transduced arteries also showed 80% greater lumen area 28 days after injury (P<0.01).

Conclusions— The effectiveness of COX-1 in preventing restenosis and preserving normal blood flow 28 days after injury results from increased lumen area caused by durable vasodilation. COX-1 efficacy correlates with an early increase in the production of PGI₂, PGE₂, PGE₁ (known to cause vasodilation), and cAMP. These results demonstrate for the first time that COX-1 gene transduction is an effective treatment for the prevention of postangioplasty restenosis of atherosclerotic arteries under clinically relevant conditions.

Key Words: blood flow • gene therapy • angioplasty • thrombus • prostaglandins