A novel pathogenetic mechanism of hypoxic pulmonary hypertension: decreased insulin sensitivity in pulmonary arterial hypertension

AIM:To investigate the underlying molecular mechanisms responsible for vascular insulin resistance (VIR) in pulmonary arterial hypertension (PAH). METHODS: Fourteen male Sprague Dawley rats were randomly divided into two groups: normal group and hypoxic pulmonary hypertension (HPH) group (exposed in hypobaric and hypoxia condition for 4 weeks). Pulmonary arterial pressure (PAP) and insulin-induced vasodilation effects of pulmonary artery rings were measured. Primary rat pulmonary microvascular endothelial cells (PMVEC) were cultured, respectively, in normal oxygen (21% O2, 37℃) and low oxygen (10% O2, 37℃) incubators. After cultured at 6, 24, 48, 96 h, cells were collected to detect the expression of TRB3, PPAR-γ and insulin signaling proteins by Western blot. Culture supernatant was used to detect generation of nitric oxide (NO). RESULTS: Compared with those in the control group, mPAP was significantly enhanced in the HPH group, whereas insulin-induced vasorelaxation reaction was significantly attenuated (n=7, P<0.05 of P<0.01). Compared with that in the normoxic group, NO level significantly increased after 6 h, declined after 24 h in the HPH group and further decreased with prolonged hypoxia. Such trends of NO changes were consistent with the expressions of PI3K-p85, p-Akt, p-eNOS but contrary to those of p-ERK1/2. In addition, TRB3 was distinctly overexpressed, whereas PPAR-γ expression decreased. CONCLUSION: Hypoxia induces overexpression of TRB3 in rat PMVEC, which negatively regulates PPAR-γ, leading to the imbalance of insulin signaling pathways and then dysfunction of PMVEC, thus contributing to the development of PHP.