Expression and analyses of the HIF-1 pathway in the lungs of humans with pulmonary arterial hypertension

摘要

Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction and structural remodeling of the pulmonary vasculature, mediated initially by reduced oxygen availability in the lungs. Hypoxia inducible factor (HIF), consisting of the functional subunit, HIF-1 alpha, and the constitutively expressed HIF-1 beta, is involved in the pathological processes associated with hypoxia. In the current study, the sequences of cDNAs and amino acids of HIF were characterized and analyzed using online bioinformatics tools. To further evaluate whether HIF accounts for the occurrence of PAH, the present study determine the expression and phosphorylation levels of HIF and its associated pathways, including extracellular signal-regulated kinase (Erk) 1/2 and phosphoinositide 3-kinase (PI3K)/Akt, in the lungs of patients with PAH by reverse transcription-quantitative polymerase chain reaction and western blotting. The mRNA expression levels of PI3K, Erk2, and HIF-1 alpha in the patients with PAH were significantly higher, compared with those in the control group, by 3.6-fold (P<0.01), 4.06-fold and 2.64-fold (P<0.05), respectively. No significant differences were found in the mRNA and protein levels of Akt between the two groups (P>0.05). The protein levels of phosphorylated (p-) Akt, Erk1/2, p-Erk1/2, HIF-1 alpha and HIF-1 beta were significantly increased by 5.89-, 0.5-, 0.59-, 1.46- and 0.92-fold, respectively, in the patients with PAH, compared with those in the controls group (P<0.01 for p-Akt, Erk1/2; P<0.05 for p-Erk1/2, HIF-1 alpha and HIF-1 beta) . These findings suggested that the mitogen-activated protein kinase and PI3K/Akt signaling pathways, and HIF-1 may perform a specific function in the pathogenesis of PAH.