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(Hypertension. 2007;50:531.)
© 2007 American Heart Association, Inc.

Original Articles

Adenoassociated Virus–Mediated Prostacyclin Synthase Expression Prevents Pulmonary Arterial Hypertension in Rats

Takayuki Ito; Takashi Okada; Jun Mimuro; Hiroshi Miyashita; Ryosuke Uchibori; Masashi Urabe; Hiroaki Mizukami; Akihiro Kume; Masafumi Takahashi; Uichi Ikeda; Yoichi Sakata; Kazuyuki Shimada; Keiya Ozawa

From the Divisions of Genetic Therapeutics (T.I., R.U., M.U., H.M., A.K., K.O.), Cardiovascular Medicine (T.I., H.M., K.S.), and Cell and Molecular Medicine (J.M.,Y.S.), Jichi Medical University, Tochigi, Japan; the Department of Molecular Therapy (T.O.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; and the Department of Organ Regeneration (M.T., U.I.), Shinshu University Graduate School of Medicine, Matsumoto, Japan.

Correspondence to Takayuki Ito or Keiya Ozawa, Division of Genetic Therapeutics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. E-mail titou{at}jichi.ac.jp or kozawa@jichi.ac.jp

Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibility of intramuscular injection of an adenoassociated virus (AAV) vector expressing PGIS for preventing monocrotaline-induced pulmonary arterial hypertension in rats. We developed an AAV serotype 1–based vector carrying a human PGIS gene (AAV-PGIS). AAV-PGIS or the control AAV vector expressing enhanced green fluorescent protein was injected into the anterior tibial muscles of 3-week–old male Wistar rats; this was followed by the monocrotaline administration at 7 weeks. Eight weeks after injecting the vector, the plasma levels of 6-keto-prostaglandin F₁ increased in a vector dose-dependent manner. At this time point, the PGIS transduction (1x10¹⁰ genome copies per body) significantly decreased mean pulmonary arterial pressure (33.9±2.4 versus 46.1±3.0 mm Hg; P<0.05), pulmonary vascular resistance (0.26±0.03 versus 0.41±0.03 mm Hg · mL^–1 · min^–1· kg^–1; P<0.05), and medial thickness of the peripheral pulmonary artery (14.6±1.5% versus 23.5±0.5%; P<0.01) as compared with the controls. Furthermore, the PGIS-transduced rats demonstrated significantly improved survival rates as compared with the controls (100% versus 50%; P<0.05) at 8 weeks postmonocrotaline administration. An intramuscular injection of AAV-PGIS prevents monocrotaline-pulmonary arterial hypertension in rats and provides a new therapeutic alternative for preventing pulmonary arterial hypertension in humans.

Key Words: hypertension • pulmonary • gene therapy • remodeling • prostacyclin synthase

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