The Role Of Adiponectin In The Development Of Hypoxic Pulmonary Hypertension And Its Mechanism

AIM: Hypoxic pulmonary hypertension is one of the common types of pulmonary hypertension, which is caused by various and complicated conditions, and usually lead to right heart failure and death. Therefore, it is urgent to clarify its pathogenesis and to provide experimental basis for its prevention and treatment. The aim of this research is to observe the effects of recombinant human globular adiponectin(g Ad) on the diastolic function of isolated pulmonary artery from rats with hypoxic pulmonary hypertension(HPH), and to confirm whether and how adiponectin(APN) improves pulmonary artery endothelial function.METHODS: 24 male SD rats were divided randomly into three groups: control group, 2-week HPH(HPH2W) group and 4-week HPH(HPH4W) group. The rats in controlgroup were maintained in normal environments and the rats in hypoxia groups were made HPH models using intermittent hypobaric hypoxia method. After establishing the hypoxia models, the mean pulmonary artery pressure(m PAP) and mean right ventricular pressure(m RVP) were measured using right cardiac catheter. The weight ratio of right ventricle and left ventricle+ventricular septum(RV/LV+S) and the weight ratio of right ventricle and body weight(RV/BW) were also measured. The APN and NO concentrations in blood serum were detected using ELISA detection kit. The microstructure changes of pulmonary small artery were observed after H&E staining on the inferior lobe of the right lung. The rat's left and right pulmonary artery trunks were taken to make vascular circles, then the isolated perfusion experiment was carried on and the vascular diastolic function induced by acetylcholine and sodium nitroprussiate under varied concentrations was observed. The pulmonary artery trunks were taken outside the lungs from mice in HPH4 W group and were incubated by grouping(HPH4W group: incubated in Krebs fluid, HPH4W+ g Ad group: incubated in g Ad 2?g/ml, HPH4W+ g Ad +L-NAME group: incubated in g Ad 2?g/ml+L-NAME 0.5mmol/L). After incubation, the author observed the vascular diastolic functions induced by acetylcholine and sodium nitroprussiate under varied concentrations. Then, the perfusate was collected in which NO production was measured. The author took the pulmonary arterial vessels from mice in HPH4 W group, divided them into groups according to the above method, incubated them and then conducted Western blot to detect the expressions and phosphorylation levels of AMPK, Akt and e NOS.RESULTS: Compared with those in control group, m PAP, m RVP, RV/LV+S and RV/BW all significantly increased(P<0.05) and the levels of serum APN and NO decreased(P<0.05). Under light microscope, smooth muscles and elastic fiber layer of pulmonary artery proliferated. The wall of the vessels thickened and lumen of the vessels narrowed. Compared with those in control group, the vascular diastolic functions of the pulmonary artery in HPH rats induced by acetylcholine decreased significantly(P<0.05). The maximal diastolic rate was 69.9% in control group, 48.8% in HPH2 W group and only 42.1% in HPH4 W group. After g Ad incubation in vitro, the diastolic function dependent on vascular circle endothelium increased significantly, the maximal diastolic rate reached 46.4% in HPH4 W group and the vascular circle diastolic function in L-NAME group wasobviously blocked. The reflection of vasodilation of rats induced by sodium nitroprussiate in all three groups was sound, with no statistically significant difference(P>0.05). Through g Ad incubation, the phosphorylation levels of AMPK, Akt and e NOS of the vascular circle tissue and the NO production of perfusate all increased(P<0.05). L-NAME blocked the effect of g Ad to increase e NOS phosphorylation and NO level.CONCLUSION: APN has significantly improved the endothelium dependent vascular relaxation of pulmonary artery of rats with intermittent hypoxic pulmonary hypertension. The mechanism was possibly through the activation of AMPK/Akt/e NOS/NO signaling pathway. These results suggested that APN may be a potential adjuvant drug for the treatment of hypoxic pulmonary hypertension.