Local gene transduction of cyclooxygenase-1 increases blood flow in injured atherosclerotic rabbit arteries.
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.


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.
Liu
Qi
Q
Wafic Said Molecular Cardiology and Gene Therapy Research Laboratory, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston 77225-0345, USA.
Chen
Zhi-Qiang
ZQ
Bobustuc
George C
GC
McNatt
Janice M
JM
Segall
Harry
H
Pan
Su
S
Willerson
James T
JT
Zoldhelyi
Pierre
P
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy*; D020212:Carotid Artery Injuries / Q000188:drug therapy*; D016893:Carotid Stenosis / Q000517:prevention & control; D000242:Cyclic AMP / Q000096:biosynthesis; D051545:Cyclooxygenase 1; D015316:Genetic Therapy / Q000379:methods; D011451:Prostaglandin-Endoperoxide Synthases / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects*; D014161:Transduction, Genetic / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects
D011453:Prostaglandins; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases