Expression and role of factor inhibiting hypoxia-inducible factor-1 in pulmonary arteries of rat with hypoxia-induced hypertension

Abstract

Hypoxia-inducible factor-1alpha subunit (HIF-1alpha) plays a pivotal role during the development of hypoxia-induced pulmonary hypertension (HPH) by transactivating it' target genes. As an oxygen-sensitive attenuator, factor inhibiting HIF-1 (FIH) hydroxylates a conserved asparagine residue within the C-terminal transactivation domain of HIF-1alpha under normoxia and moderate hypoxia. FIH protein is downregulated in response to hypoxia, but its dynamic expression and role during the development of HPH remains unclear. In this study, an HPH rat model was established. The mean pulmonary arterial pressure increased significantly after 7 d of hypoxia. The pulmonary artery remodeling index became evident after 7 d of hypoxia, while the right ventricular hypertrophy index became significant after 14 d of hypoxia. The messenger RNA (mRNA) and protein expression of HIF-1alpha and vascular endothelial growth factor (VEGF), a well-characterized target gene of HIF-1alpha, were markedly upregulated after exposure to hypoxia in pulmonary arteries. FIH protein in lung tissues declined after 7 d of hypoxia and continued to decline through the duration of hypoxia. FIH mRNA had few changes after exposure to hypoxia compared with after exposure to normoxia. In hypoxic rats, FIH protein showed significant negative correlation with VEGF mRNA and VEGF protein. FIH protein was negatively correlated with mean pulmonary arterial pressure, pulmonary artery remodeling index and right ventricular hypertrophy index. Taken together, our results suggest that, in the pulmonary arteries of rat exposed to moderate hypoxia, a time-dependent decrease in FIH protein may contribute to the development of rat HPH by enhancing the transactivation of HIF-1alpha target genes such as VEGF.

Network Pharmacology and Molecular Docking Analysis of Shufeiya Recipe in the Treatment of Pulmonary Hypertension

“…The top 30 signaling pathways are shown in Figure 2(c) . Previous studies have reported that the PI3K-AKT signaling pathway [ 17 ], IL-17 signaling pathway [ 18 ], TNF pathway [ 19 ], MAPK signaling pathway [ 20 ], HIF-1 signaling pathway [ 21 ], and Toll-like receptor signaling pathway [ 22 ] were related to the occurrence of PH, among which the PI3K-AKT pathway was most closely related to the treatment of PH with Shufeiya recipe ( Figure 3 ).…”

“…ERK activation can promote the proliferation of pulmonary artery fibroblasts, while Shufeiya recipe can downregulate the expression levels of Ras, p-MEK1/2, p-ERK1/2, and c-fos proteins in the ERK signaling pathway, thereby inhibitting PAECs fibrosis [ 5 ]. Activation of the HIF-1 signaling pathway in PAECs can promote the proliferation of pulmonary artery medial cells, and the expression of factors such as endothelin 1 [ 21 , 29 ]. The Toll-like receptor signaling pathway is closely related to the proliferation, apoptosis, migration, and interstitial transition of PAECs [ 22 , 30 ].…”