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Title: [Differential expression of the three hypoxia-inducible factor alpha subunits in pulmonary artery of rats with hypoxia-induced pulmonary hypertension].
Author: Li QF, Dai AG.
Journal: Zhonghua Jie He He Hu Xi Za Zhi; 2006 Feb; 29(2):113-7. PubMed ID: 16677454.
Abstract:
OBJECTIVE: To differentiate the expression patterns of all hypoxia-inducible factor alpha (HIF-alpha) subunits (HIF-1alpha, HIF-2alpha and HIF-3alpha) in pulmonary artery of rats undergoing systemic hypoxia. METHODS: Forty male healthy wistar rats were assigned randomly to 5 groups, 8 rats per group, then exposed to hypoxia [O2, (10.0 +/- 0.5)%] for 0 d (H(0)), 3 d (H(3)), 7 d (H(7)), 14 d (H(14)) and 21 d (H(21)) respectively, 8 h per day intermittently. Mean pulmonary arterial pressure (mPAP), arterial wall area (WA, microm), pulmonary artery medium thickness (PAMT%) and right ventricle hypertrophy index (RVHI) were measured. HIF-1alpha, HIF-2alpha and HIF-3alpha gene expression were determined by immunohistochemistry, in situ hybridization and Western blot. RESULTS: mPAPs in H(7), H(0) and H(14) groups were [(18.40 +/- 0.40) mm Hg, 1 mm Hg = 0.133 kPa], [(14.40 +/- 0.40) mm Hg] and [(21.20 +/- 0.20) mm Hg], respectively, statistically different when H(7) group was compared with H(0) and H(14) groups (all P < 0.05). Arterial morphology showed that WA%, PAMT and RVHI% in H(7) group were (47.8 +/- 0.8)%, (12.3 +/- 0.5) microm, (24.0 +/- 1.0)%, respectively; in H(0) group were (35.5 +/- 1.3)%, (11.9 +/- 0.6)%, (23.6 +/- 0.5) microm, respectively; in H(21) group were (65.0 +/- 0.7)%, (23.0 +/- 0.8) microm, (27.7 +/- 1.0)%, respectively. When H(7) group was compared with H(0) group, only WA% was statistically different; when H(14) group was compared with H(0) group, all the three parameters were statistically different (P < 0.05). In situ hybridization demonstrated that the mRNA levels (absorbance, A) of HIF-1alpha, HIF-2alpha, and HIF-3alpha in H(14) group were 0.200 +/- 0.020, 0.080 +/- 0.010, 0.170 +/- 0.010, respectively; in H(7) group were 0.050 +/- 0.020, 0.160 +/- 0.020, 0.160 +/- 0.020, respectively; in H(0) group were 0.050 +/- 0.010, 0.140 +/- 0.020, 0.060 +/- 0.010, respectively. When H(7) group was compared with H(0) group, only HIF-3alpha was statistically different; when H(14) group was compared with H(0) group, all the three genes were significantly different (P < 0.05). Immunohistochemistry showed that HIF-1alpha, HIF-2alpha and HIF-3alpha protein levels in H(3) group were 0.200 +/- 0.020, 0.020 +/- 0.010, 0.050 +/- 0.010, respectively; in H(14) group were 0.160 +/- 0.010, 0.100 +/- 0.020, 0.160 +/- 0.010, respectively; in H(7) group were 0.220 +/- 0.020, 0.030 +/- 0.010, 0.180 +/- 0.020, respectively; in H(0) group were 0.050 +/- 0.010, 0.020 +/- 0.010, 0.040 +/- 0.010, respectively. HIF-1alpha in H(3) group, HIF-2alpha in H(14) group, HIF-3alpha in H(7) and H(3) group were statistically different with that of H(0) group (P < 0.05). Protein bands of HIF-alpha subunits in lung tissue, measured by Western blot, showed that HIF-3alpha decreased in H(7) group as compared to H(0) group, but the other two proteins showed a marked increase in H(3) group as compared to H(0) group, and increased further corresponding to the duration of hypoxia and peaked in H(14) group as compared to H(7) group. CONCLUSION: The differential expression of the three HIF-alpha subunits may play a role in the development of hypoxia-induced pulmonary hypertension.

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