Increased Expression of Hypoxia-Inducible Factor-1α in Proliferating Neointimal Lesions in a Rat Model of Pulmonary Arterial Hypertension

Abstract

IntroductionThe role of hypoxia-inducible factor-1α (HIF-1α) in pulmonary vascular remodeling is still undetermined. The objective of this study is to investigate the expression of HIF-1α and its role in proliferating neointimal lesions in a rat model of pulmonary arterial hypertension induced by monocrotaline (MCT) administration after left pneumonectomy. MethodsThe rats were subjected to MCT (60mg/kg, subcutaneously) 7days after left pneumonectomy or sham surgery; controls with vehicle treatment after left pneumonectomy or sham surgery were also studied. On day 35, hemodynamic parameters of the rats were measured. The right lower lobes of the lungs were fixed for morphometric analysis. The expression of proliferating cell nuclear antigen and survivin was detected with Western blot. The expressions of HIF-1α and hexokinase-2 (HK-2) were detected with Western blot and immunohistochemistry assay. ResultsThe rats treated with MCT after pneumonectomy developed severe pulmonary arterial hypertension and marked medial thickening on day 35. The neointimal lesions in pulmonary arterioles were observed only in MCT-treated pneumonectomized rats. The severely injured pulmonary arterioles (intimal proliferation causing greater than 50% luminal occlusion) accounted for 40% of all the measured arterioles in rats treated by MCT after pneumonectomy. The intriguing finding showed that HIF-1α was predominantly expressed in neointimal lesion areas, paralleled with the increased expression of HK-2 in MCT-treated pneumonectomized rats, which was not observed in rats undergoing MCT treatment alone. ConclusionsThe activation of HIF-1α/HK-2 axis is probably the key mediator responsible for the neointimal lesion formation in MCT-treated pneumonectomized rats.