| AIM: To investigate the changes of insulin sensitivity of pulmonary artery in hypoxicpulmonary hypertension(HPH) rats and the influence of pioglitazone (PIO) treatment atdifferent stages of the disease process and to analyze the role of insulin resistance in thedevelopment of hypoxic pulmonary hypertension.METHODS: Twenty-eight male SD rats were randomly divided into four equal groups:normal group, HPH group, HPH1week+PIO group and HPH3weeks+PIO group. Rats inHPH group, HPH1week+PIO group and HPH3weeks+PIO group were exposed tolow-pressure and low-oxygen condition in an auto-modulating hypobaric and hypoxiccabin (8hours every day for4weeks) to establish HPH the animal model. HPH1week+PIO group and HPH3weeks+PIO group were treated with PIO (10mg/kg/d) in thesecond week and fourth week respectively. After4-week low-pressure and low-oxygenexposure, glucometer and ELISA method were used respectively to determinate the levelof fasting blood glucose (FBG) and fasting serum insulin (FSI),then the insulin resistanceindex (IRI) was calculated. A micro-catheter was inserted into right ventricle andpulmonary artery through right external jugular vein, and the mean pulmonary arterialpressure (mPAP) and mean right ventricular pressure (mRVP) were measured, then rightventricle index (RVI) was calculated. The changes of pulmonary vascular microstructurewere observed through HE staining and elastic tissue staining. the microscopic images were analyzed by computerized morphometric systemand.The external diameter (ED),medial wall thickness (MT),medial cross-sectional area (MA) and total arterialcross-sectional area (TAA) of peripheral pulmonary artery were measured. ThenMT%,MA%were calculated. The main pulmonary artery was isolated from rat.Vasodilation effect of insulin on pulmonary artery rings pre-treated with phenephrine (PE)was investigated by perfusion technique in vitro. Western Blot was applied to detemine theexpression of TRB3,PPARγ,PI3K-p85,Akt,p-Akt eNOS and p-eNOS in pulmonary artery.RESULTS: Compared with those in control group, fasting serum insulin (FSI), insulinresistance index (IRI), mean pulmonary arterial pressure (mPAP), right ventricularpressure (RVP) and right ventricle index (RVI) were significantly enhanced in HPH group(P<0.05). HE staining showed hyperplasia in pulmonary artery wall thickening and vesselstenosis. MT%,MA%were significantly increased (P<0.05).Insulin inducedvasorelaxation reaction was significantly attenuated (P<0.05).The expression level ofTRB3was higher, the expression level of PPARγ, PI3K-p85, p-Akt, p-eNOS weredecreased in pulmonary artery(P<0.05). Compared with those in HPH group, fastingblood-glucose (FBG), FSI, IRI, mPAP, mRVP and RVI decreased in HPH1week+PIOgroup (P<0.05). Wall thickening and vessel stenosis were significantly reduced andMT%,MA%were significantly decreased (P<0.05).insulin induced vasorelaxationreaction was also significantly improved (P<0.05).The expression level of TRB3waslower, the expression level of PPARγ, PI3K-p85, p-Akt, p-eNOS were significantlyincreased in pulmonary artery (P<0.05).However, compared with these changes, nosignificant difference was observed in HPH3weeks+PIO group (P>0.05).CONCLUSION: Attenuated insulin sensitivity of pulmonary artery occurrs in the earlystage of hypoxic pulmonary hypertension, which maybe correlated with the upregulationof TRB3and PPARgamma decrease induced by the impairment ofPI3-kinase/Akt/eNOS-mediated signaling. Early for insulin sensitization of pioglitazonetreatment, can effectively improve pulmonary vascular of diastolic dysfunction andpulmonary vascular remodeling, and significantly lower pulmonary artery pressure, whilethe late treatment of pulmonary vasodilation function and pulmonary arterial pressure has no obvious improvement.Vascular insulin resistance of pulmonary artery plays animportant role in the development of hypoxia-induced pulmonary hypertension,suggesting that early treatment targeting insulin-induced vasodilation is possibly of valuefor the pulmonary hypertension. |
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