Nagaya N, Yokoyama C, Kyotani S, Shimonishi M, Morishita R, Uematsu M, Nishikimi T, Nakanishi N, Ogihara T, Yamagishi M, Miyatake K, Kaneda Y, Tanabe T
Division of Cardiology, Department of Medicine, National Cardiovascular Center, Osaka University Medical School, Osaka, Japan.
Circulation. 2000 Oct 17;102(16):2005-10. doi: 10.1161/01.cir.102.16.2005.
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.
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 x mL x min(-1) x 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-PGF(1alpha), 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).
Intratracheal transfer of the human PGIS gene augmented pulmonary prostacyclin synthesis, ameliorated MCT-induced pulmonary hypertension, and thereby improved survival in MCT rats.
前列环素是一种强效血管舒张剂，还可抑制血小板黏附和细胞生长。我们研究了人前列环素合酶（PGIS）的体内基因转移是否能改善大鼠中野百合碱（MCT）诱导的肺动脉高压。
通过日本血凝病毒-脂质体法将编码PGIS的cDNA经气管转染至大鼠肺内。转染缺乏PGIS基因的对照载体的大鼠作为对照。注射MCT三周后，平均肺动脉压和总肺阻力显著升高；与对照组相比，PGIS基因转染大鼠的升高显著减弱[平均肺动脉压，31±1对35±1 mmHg（-12%）；总肺阻力，0.087±0.01对0.113±0.01 mmHg·mL·min⁻¹·kg⁻¹（-23%），均P<0.05]。体动脉压和心率未受影响。组织学上，PGIS基因转移抑制了MCT注射导致的外周肺动脉中膜厚度增加。PGIS免疫反应主要在支气管上皮和肺泡细胞中强烈。PGIS基因转移后≥1周，前列环素的稳定代谢产物6-酮-PGF(1α)的肺组织水平显著升高。Kaplan-Meier生存曲线表明，每2周重复转移PGIS基因可提高MCT大鼠的生存率（对数秩检验，P<0.01）。
人PGIS基因的气管内转移增加了肺前列环素的合成，改善了MCT诱导的肺动脉高压，从而提高了MCT大鼠的生存率。
