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(Circulation. 2001;103:2090.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Selective Augmentation of Prostacyclin Production by Combined Prostacyclin Synthase and Cyclooxygenase-1 Gene Transfer

Song-Kun Shyue, PhD; May-Jywan Tsai, PhD; Jun-Yang Liou, PhD; James T. Willerson, MD; Kenneth K. Wu, MD, PhD

From the Vascular Biology Program, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (S-K.S., M-J.T., J-Y.L., K.K.W.), and Vascular Biology Research Center and Department of Internal Medicine, University of Texas–Houston Medical School, Houston, Tex (J.T.W., K.K.W.).

Correspondence to Dr Kenneth K. Wu, Division of Hematology, University of Texas–Houston Medical School, 6431 Fannin, MSB 5.016, Houston, TX 77030. E-mail Kenneth.K.Wu{at}uth.tmc.edu

Background—We tested the hypothesis that combined cyclooxygenase-1 (COX-1) and prostacyclin synthase (PGIS) gene transfer selectively augments prostacyclin production without a concurrent overproduction of other prostanoids.

Methods and Results—ECV304 cells were transfected with bicistronic pCOX-1/PGIS versus pCOX-1 or pPGIS, and prostanoids were analyzed. Contrary to the high prostaglandin E₂ synthesis in pCOX-1 transfected cells, selective prostacyclin formation was noted with bicistronic plasmid transfection. Next, we determined the optimal ratio of Ad-COX-1 to Ad-PGIS by transfecting human umbilical vein endothelial cells with various titers of these 2 adenoviral constructs and determined the level of protein expression and prostanoid synthesis. Our results show that optimal ratios of adenoviral titers to achieve a large prostacyclin augmentation without overproduction of prostaglandin E₂ or F₂ were 50 to 100 plaque forming units (pfu) of Ad-COX-1 to 50 pfu of Ad-PGIS per cell. A higher Ad-PGIS to Ad-COX-1 ratio caused a paradoxical decline in prostacyclin synthesis.

Conclusions—Prostacyclin synthesis can be selectively augmented by cotransfecting endothelial cells with an optimal ratio of COX-1 to PGIS. Combined COX-1 and PGIS gene transfer has the potential for therapeutic augmentation of prostacyclin.

Key Words: gene therapy • prostaglandins • hypertension, pulmonary • heart diseases

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