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

Article

关键词: GAMMA-LINOLENIC ACID;    RAT CAROTID-ARTERY;    ENDOTHELIAL PROGENITOR CELLS;    PROLIFERATION IN-VIVO;    CIS-ELEMENT DECOY;    NEOINTIMA FORMATION;    BALLOON INJURY;    INTIMAL HYPERPLASIA;    CORONARY-ARTERIES;    CONTROLLED-TRIAL;   

DOI  :  10.1161/01.CIR.0000158480.28733.89

来源: SCIE

【 摘 要 】

Background-Cyclooxygenase-1 (COX-1) is the rate-limiting component in the synthesis of prostacyclin (PGI(2)), an important vasodilator and antithrombotic molecule. In balloon-injured, atherosclerosis-free porcine arteries, COX-1 gene transduction increases PGI(2) 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 PGI(2) (P<0.01), 400% more prostaglandin E-2 (PGE(2)) (P<0.01), 400% more prostaglandin E-1 (PGE(1)) (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 PGI(2), PGE(2), PGE(1) ( 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.

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