3091

HIF1A

HIF-1A|HIF-1alpha|HIF1|HIF1-ALPHA|MOP1|PASD8|bHLHe78;hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor);HIF1A;hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)

ARNT interacting protein|ARNT-interacting protein|HIF-1-alpha|PAS domain-containing protein 8|basic-helix-loop-helix-PAS protein MOP1|class E basic helix-loop-helix protein 78|hypoxia-inducible factor 1 alpha isoform I.3|hypoxia-inducible factor 1, alpha

14q23.2

protein-coding

Count: Hif1a; 29560

AIM: To investigate the dynamic expression of hypoxia-inducible factor 1alpha, PHDs and OS-9 in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. METHODS: SD rats were randomly divided into 5 groups (n = 8) and exposed to hypoxia for 0, 3, 7, 14 or 21 d, respectively. RT-PCR and in situ hybridization were used to determine the expression of mRNA. Immunohistochemistry and Western blot were used to determine the expression of protein. RESULTS: HIF-1alpha protein was poorly positive in control, markedly up-regulated after 3 d and 7 d of hypoxia (P < 0.05, vs group C), and then declined slightly after 14 d and 21 d of hypoxia. HIF-1alpha mRNA increased dramatically after 14 d of hypoxia (P < 0.05, vs group C). PHD1, PHD2 mRNA and protein was positive in group C. PHD2 mRNA and protein were up-regulated after 3 d of hypoxia (P < 0.05, vs group C), reaching its peak after 14 d of hypoxia while PHD1 protein declined after 14 d of hypoxia (P < 0.05, vs group C) without statistic mRNA changing. PHD3 mRNA and protein were detected at low level in control, markedly up-regulated after 3 d of hypoxia (P < 0.05, vs group C), and then PHD3 mRNA kept at high level while PHD3 protein declined after 14 d of hypoxia (P < 0.05, vs 7 d). OS-9 mRNA was positively in control, markedly decreased after 3 d of hypoxia (P < 0.05, vs group C), reaching its lowest lever after 14 d of hypoxia. Linear correlation analysis showed that OS-9 protein was positively correlated with OS-9 mRNA (r = 0.82, P < 0.01) and HIF-1alpha protein (r = 0.57, P < 0.01). CONCLUSION: HIF-1alpha, PHDs and OS-9 are all involved in the pathogenesis of hypoxic pulmonary hypertension in rats. OS-9 may interact with both HIF-1alpha and PHDs to promote PHD-mediated hydroxylation of HIF-1alpha.

OBJECTIVE: To assess the effects of hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) on hypoxic pulmonary hypertension(HPH) in patients with acute high altitude reaction(AHAR) and its change after return to lower altitude. METHODS: Ninety-six officers and soldier participating in rescue of Yushu megaseism on April 14th in 2010, leaving low altitude area (1 500 m) rapidly to high altitude area(3 700 m) to undertake strenuous physical work were enrolled for study. All of them were male, aged 18-35 years, and they were divided into three groups according to the symptomatic scores of AHAR: without AHAR(group B, n=25), mild to moderate AHAR (group C, n=47 ) and severe AHAR (group D, n=24). Mean pulmonary artery pressure (mPAP), levels in serum HIF-1alpha and VEGF were measured at high altitude area after a stay of 50 days, and also after their return to lower altitude area (1 500 m) for 12 hours and 15 days. Fifty healthy volunteers at low altitude area served as control (group A). RESULTS: Level of mPAP (mm Hg, 1 mm Hg=0.133 kPa), serum HIF-1alpha (pg/L) and VEGF (ng/L) in group B (24.23+/-1.56, 68.80+/-7.52 and 82.56+/-6.32) were significantly higher than those in group A (18.50+/-1.30, 50.95+/-3.33 and 65.78+/-4.03), respectively (all P<0.01). Moreover, the value of all the parameters increased with increase in severity of AHAR, the respective value in group C were 28.42+/-1.32, 88.10+/-9.20 and 104.82+/-10.36, and in group D were 34.70+/-2.94, 117.93+/-13.46 and 136.77+/-12.03, and there were significant differences in comparing two groups (all P<0.01). At high altitude area, AHAR total score was positively correlated with mPAP, serum HIF-1alpha and VEGF (r=0.672, 0.737 and 0.634, respectively, all P<0.01), mPAP was positively correlated with serum HIF-1alpha and VEGF (r=0.706, 0.638, both P<0.01). Compared with group A, level of mPAP (29.08+/-4.22), serum HIF-1alpha (91.16+/-20.58) and VEGF (107.11+/-10.32) were significantly increased in 96 officers and soldiers who stayed for 50 days at an altitude of 3 700 m (all P<0.01), and the values were significantly decreased after returning to lower altitude area for 12 hours(23.05+/-3.18, 70.99+/-8.22 and 78.65+/-6.47) and 15 days(18.96+/-1.75, 52.31+/-4.92 and 63.08+/-4.55). The values showed significant difference between 12 hours and 15 days stay at 1 500 m (all P<0.01). The values of the determined parameters 15 days after return to lower altitude area showed no difference compared with those of group A (all P>0.05). CONCLUSION: Strenuous physical work at high altitude area, AHAR becomes more serious, and it is accompanied by higher values of HIF-1alpha, VEGF and mPAP, indicating that HPH is closely associated with elevation of HIF-1alpha and VEGF. These changes are improved after returning to lower altitude area for 12 hours, and they recover to normal lever after 15 days.

INTRODUCTION: The role of hypoxia-inducible factor-1alpha (HIF-1alpha) in pulmonary vascular remodeling is still undetermined. The objective of this study is to investigate the expression of HIF-1alpha and its role in proliferating neointimal lesions in a rat model of pulmonary arterial hypertension induced by monocrotaline (MCT) administration after left pneumonectomy. METHODS: The rats were subjected to MCT (60 mg/kg, subcutaneously) 7 days 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-1alpha and hexokinase-2 (HK-2) were detected with Western blot and immunohistochemistry assay. RESULTS: The 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-1alpha 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. CONCLUSIONS: The activation of HIF-1alpha/HK-2 axis is probably the key mediator responsible for the neointimal lesion formation in MCT-treated pneumonectomized rats.

INTRODUCTION: The role of hypoxia-inducible factor-1alpha (HIF-1alpha) in pulmonary vascular remodeling is still undetermined. The objective of this study is to investigate the expression of HIF-1alpha and its role in proliferating neointimal lesions in a rat model of pulmonary arterial hypertension induced by monocrotaline (MCT) administration after left pneumonectomy. METHODS: The rats were subjected to MCT (60 mg/kg, subcutaneously) 7 days 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-1alpha and hexokinase-2 (HK-2) were detected with Western blot and immunohistochemistry assay. RESULTS: The 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-1alpha 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. CONCLUSIONS: The activation of HIF-1alpha/HK-2 axis is probably the key mediator responsible for the neointimal lesion formation in MCT-treated pneumonectomized rats.