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(Circulation. 2000;102:2005.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

Noritoshi Nagaya, MD; Chieko Yokoyama, PhD; Shingo Kyotani, MD; Manabu Shimonishi, PhD; Ryuichi Morishita, MD; Masaaki Uematsu, MD; Toshio Nishikimi, MD; Norifumi Nakanishi, MD; Toshio Ogihara, MD; Masakazu Yamagishi, MD; Kunio Miyatake, MD; Yasufumi Kaneda, MD; Tadashi Tanabe, PhD

From the Division of Cardiology, Department of Medicine, National Cardiovascular Center (N. Nagaya, S.K., M.U., T.N., N. Nakanishi, M.Y., K.M.); Department of Pharmacology, National Cardiovascular Center Research Institute (C.Y., M.S., T.T.); and Departments of Gene Therapy Science (R.M., Y.K.) and Geriatric Medicine (T.O.), Osaka University Medical School, Osaka, Japan.

Background—Prostacyclin is a potent vasodilator that also inhibits platelet adhesion and cell growth. We investigated whether in vivo gene transfer of human prostacyclin synthase (PGIS) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats.

Methods and Results—The cDNA encoding PGIS was intratracheally transfected into the lungs of rats by the hemagglutinating virus of Japan–liposome method. Rats transfected with control vector lacking the PGIS gene served as controls. Three weeks after MCT injection, mean pulmonary arterial pressure and total pulmonary resistance had increased significantly; the increases were significantly attenuated in PGIS gene–transfected rats compared with controls [mean pulmonary arterial pressure, 31±1 versus 35±1 mm Hg (-12%); total pulmonary resistance, 0.087±0.01 versus 0.113±0.01 mm Hg · mL · min^-1 · kg^-1 (-23%), both P<0.05]. Systemic arterial pressure and heart rate were unaffected. Histologically, PGIS gene transfer inhibited the increase in medial wall thickness of peripheral pulmonary arteries that resulted from MCT injection. PGIS immunoreactivity was intense predominantly in the bronchial epithelium and alveolar cells. Lung tissue levels of 6-keto-PGF₁, a stable metabolite of prostacyclin, were significantly increased for 1 week after transfer of PGIS gene. The Kaplan-Meier survival curves demonstrated that repeated transfer of PGIS gene every 2 weeks increased survival rate in MCT rats (log-rank test, P<0.01).

Conclusions—Intratracheal transfer of the human PGIS gene augmented pulmonary prostacyclin synthesis, ameliorated MCT-induced pulmonary hypertension, and thereby improved survival in MCT rats.

Key Words: prostaglandins • gene therapy • hypertension, pulmonary • viruses

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