Effects Of Iptakalim On The Mrna And Protein Expression Of Vegf In Pulmonary Artery On Chronic Hypoxic Rats

Objective: Pulmonary arterial hypertension (PAH) is primarily characterized by increased pulmonary vascular resistance, which enventually leads to right heart failure, severe functional limitations, and ultimately death. Hypoxic pulmonary hypertension (HPH) has been demonstrated to be the key event in the process from chronic obstructive pulmonary disease (COPD) to chronic cor pulmonale. Previous study had found that the novel ATP-sensitive potassium channel opener Iptakalim (Ipt) could prevent pulmonary hypertension in chronic hypoxic rats, so the aim of this study was to investigate if any difference exists in mRNA and protein levels of VEGF in pulmonary artery between chronic hypoxic and normal rats, and to examine if any changes of VEGF mRNA and protein expression occurred after long-term Iptakalim treatment on chronic hypoxic rats. Methods: Sprague-Dawley rats were fed in hypoxic and normobaric environment (10±0.5% O2, 8h·day-1, 6day·week-1 and 4weeks) to establish HPH model. Thirty-six male SD rats were randomly divided into control group (NS 5 ml/kg·d), hypoxic group (hypoxia + NS 5 ml/kg·d), Ipt treated group (Ipt 1.5 mg/kg·d via oral gavage + hypoxia), 12 rats are in each group. Four weeks later, the mean pulmonary arterial pressure (mPAP) was measured, then the rats were executed, and main of pulmonary artery and hearts were immediately removed. The hearts were fixed for one week in 10% Formalin (PH7.40) and RV/LV+S were determined. RT-PCR and Western-blot were performed to analyze the mRNA and protein levels of VEGF in main pulmonary artery.Results: (1) The level of mPAP was significantly higher in the hypoxic group (35.89±2.26 mmHg) than that in control group (18.35±1.48 mmHg, P<0.01). In the Iptakalim treated group the level of mPAP decreased significantly (19.17±1.54 mmHg, P<0.01). (2) The level of RV/LV+S was remarkably higher in the hypoxic group (0.352±0.016) than that in control group (0.262±0.013, P<0.01). In the Iptakalim treated group the level of RV/LV+S decreased remarkably (0.282±0.034, P <0.01). (3) The VEGF mRNA was detected in main pulmonary artery of rats. The mRNA level of VEGF in the hypoxic group was significantly higher than the control group (0.83±0.02 vs 0.34±0.01, P<0.01), while in the Iptakalim treated group the expression was lower than that in the hypoxic group (0.33±0.02 vs 0.83±0.02, P<0.01). There were no differences between the control group and the treated group (P>0.05). (4) The VEGF protein was also detected in main pulmonary artery of rats. The protein level of VEGF in the hypoxic group were significantly higher than that in the control group (0.806±0.025 vs 0.413±0.070, P<0.01), while in Iptakalim treated group the level were lower than that in the hypoxic group (0.416±0.074 vs 0.806±0.025, P<0.01), There were no statistically significant changes between the control group and the treated group (P>0.05).Conclusion: The results indicate that VEGF of pulmonary artery maybe contribute to the pathogenesis of chronic hypoxia pulmonary hypertension. Ipt remarkably inhibited the expression of VEGF mRNA and protein in the hypoxic group.