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(Circulation. 2002;105:1962.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Cyclooxygenase-1 and Bicistronic Cyclooxygenase-1/Prostacyclin Synthase Gene Transfer Protect Against Ischemic Cerebral Infarction

Heng Lin, BS; Teng-Nan Lin, PhD; Wai-Mui Cheung, PhD; Gau-Ming Nian, PhD; Ping-Hui Tseng, PhD; Shu-Fen Chen, PhD; Jean-Ju Chen, PhD; Song-Kun Shyue, PhD; Jun-Yang Liou, PhD; Cheng-Wen Wu, MD PhD; Kenneth K. Wu, MD PhD

Institute of Biomedical Sciences, Academia Sinica (H.L., T-N.L. W-M.C., G-M.N., P-H.T., S-F.C., J-J.C., S-K.S., J-Y.L., C-W.W.), Taipei, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center (H.L.), Taipei, Taiwan; and Vascular Biology Research Center, Institute of Molecular Medicine and Division of Hematology, University of Texas–Houston Health Science Center (K.K.W.).

Correspondence to Dr Kenneth K. Wu, University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX 77030 (E-mail Kenneth.K.Wu{at}uth.tmc.edu) or to Dr Teng-Nan Lin, Institute of Biomedical Sciences, 128 Academy Rd, Section 2, Taipei, Taiwan (E-mail bmltn@IBMS.sinica.edu.tw).

Background— We tested the hypothesis that bicistronic cyclooxygenase-1 (COX-1)/prostacyclin synthase (PGIS) and COX-1 gene transfer reduce cerebral infarct volume by augmenting synthesis of protective prostaglandins.

Methods and Results— We infused into lateral ventricle of a rat stroke model recombinant adenoviruses (rAd) containing COX-1 (Adv-COX-1), COX-1 and PGIS (Adv-COX-1/PGIS), or Adv-PGK control vector, and we determined COX-1 and PGIS protein and eicosanoid levels and infarct volume. COX-1 and PGIS proteins were increased in a time-dependent manner. Adv-COX-1/PGIS infusion selectively augmented prostacyclin levels, with reduction of other eicosanoids in ischemic cortex and a significant reduction of infarct volume, even when the rAd was administered 5 hours after ischemia. Infusion of Adv-COX-1 also increased prostacyclin, suppressed leukotriene levels, and achieved a similar degree of cerebral protection. Its neuroprotection was abrogated by treatment with a selective COX-1 inhibitor.

Conclusions— COX-1/PGIS and COX-1 gene transfer reduce cerebral infarct volume by augmenting prostacyclin and suppressing leukotriene productions. COX-1–based gene transfer has potential for treating ischemic stroke.

Key Words: prostaglandins • genes • stroke • ischemia • gene therapy

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