Schermuly Ralph Theo, Pullamsetti Soni Savai, Kwapiszewska Grazyna, Dumitrascu Rio, Tian Xia, Weissmann Norbert, Ghofrani Hossein Ardeschir, Kaulen Christina, Dunkern Torsten, Schudt Christian, Voswinckel Robert, Zhou Jiang, Samidurai Arun, Klepetko Walter, Paddenberg Renate, Kummer Wolfgang, Seeger Werner, Grimminger Friedrich
University of Giessen Lung Centre, Justus-Liebig-Universität Giessen, Klinikstrasse 36, 35392 Giessen, Germany.
Circulation. 2007 May 1;115(17):2331-9. doi: 10.1161/CIRCULATIONAHA.106.676809. Epub 2007 Apr 16.
Pulmonary arterial hypertension (PAH) is a life-threatening disease, characterized by vascular smooth muscle cell hyperproliferation. The calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) may play a major role in vascular smooth muscle cell proliferation.
We investigated the expression of PDE1 in explanted lungs from idiopathic PAH patients and animal models of PAH and undertook therapeutic intervention studies in the animal models. Strong upregulation of PDE1C in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was noted on the mRNA level by laser-assisted vessel microdissection and on the protein level by immunohistochemistry. In chronically hypoxic mouse lungs and lungs from monocrotaline-injected rats, PDE1A upregulation was detected in the structurally remodeled arterial muscular layer. Long-term infusion of the PDE1 inhibitor 8-methoxymethyl 3-isobutyl-1-methylxanthine in hypoxic mice and monocrotaline-injected rats with fully established pulmonary hypertension reversed the pulmonary artery pressure elevation, structural remodeling of the lung vasculature (nonmuscularized versus partially muscularized versus fully muscularized small pulmonary arteries), and right heart hypertrophy.
Strong upregulation of the PDE1 family in pulmonary artery smooth muscle cells is noted in human idiopathic PAH lungs and lungs from animal models of PAH. Inhibition of PDE1 reverses structural lung vascular remodeling and right heart hypertrophy in 2 animal models. The PDE1 family may thus offer a new target for therapeutic intervention in pulmonary hypertension.
肺动脉高压（PAH）是一种危及生命的疾病，其特征为血管平滑肌细胞过度增殖。钙/钙调蛋白依赖性磷酸二酯酶1（PDE1）可能在血管平滑肌细胞增殖中起主要作用。
我们研究了PDE1在特发性PAH患者的离体肺组织以及PAH动物模型中的表达，并在动物模型中进行了治疗干预研究。通过激光辅助血管显微切割技术在mRNA水平以及通过免疫组织化学在蛋白水平上发现，与健康供体肺相比，特发性PAH肺组织中肺动脉血管的PDE1C有强烈上调。在慢性低氧小鼠肺以及注射野百合碱的大鼠肺中，在结构重塑的动脉肌层中检测到PDE1A上调。在低氧小鼠以及已完全形成肺动脉高压的注射野百合碱的大鼠中长期输注PDE1抑制剂8-甲氧基甲基3-异丁基-1-甲基黄嘌呤可逆转肺动脉压力升高、肺血管结构重塑（非肌化与部分肌化与完全肌化的小肺动脉）以及右心室肥厚。
在人类特发性PAH肺组织以及PAH动物模型的肺组织中，肺动脉平滑肌细胞中的PDE1家族有强烈上调。在两种动物模型中，抑制PDE1可逆转肺血管结构重塑以及右心室肥厚。因此，PDE1家族可能为肺动脉高压的治疗干预提供一个新靶点。
