The Role Of JNK Signaling Pathway In The Vascular Remodeling In Sleep Apnea Syndrome With Hypertension

Background and Objective:Sleep apnea syndrome( SAS) is one common clinical sleep respiratory diseases, accompanied by the night snoring, sleep apnea and daytime sleepiness symptoms, while its recurrent hypoxemia and hypercapnia state caused by typical characteristic of oxygen-oxygenation mode is one important pathophysiological mechanism of complicating hypertension, coronary heart disease, diabetes and cerebrovascular disease.Everyone could pay attention to this disease as for its potential risk of death.As basic and clinical studies about SAS and high blood pressure have been furthered so far, there are little research about vessels change on SAS combined with high blood pressure.Because JNK signaling pathway is an important fulcrum in thecell-apoptosis,stress and inflammatory response,we hypothesize that it is a key point relevant to SAS combined with hypertension.Therefore,this study is conducted to establish vasculature remodeling of abdominal artery in SAS with hypertension rats model and investigate the expression of JNK signaling pathway in model rats and the effect of JNK signaling pathway inhibitors SP600125 on vasculature remodeling of abdominal artery and their underlying pathophysiological mechanisms of vasculature remodeling of abdominal artery in rats model.Methods:48 healthy male SD rats were randomly divided into 4 groups including normoxia group, normoxia + SP600125 group,chronic intermittent hypoxia(CIH)group and chronic intermittent hypoxia +SP600125 group.Both CIH and CIH+SP600125 group were located in hypoxia cabin and subjected to intermittent circuling of nitrogen and oxygen infusion for 8h everyday in every120 s per circule,while both normoxia group were subjected to normaxia oxygen in the same cabin. The tail mean arterial systolic pressure(MAP)of all subjects were measured before the intervention and every two weeks after the intervention.Rats were sacrificed after 12 weeks, the pathologicalmorphological changes of abdominal artery were observed by HE staining, Masson staining and immunohistochemical method. TGF- β 1expression is used to identify abdominal aorta vasculature remodeling byRT-PCR method. RT-PCR and Western-blot method were used to dectect the expression of JNK-1and MCP-1 mRNA and protein in abdominal artery,exploring the role of JNK signaling pathways in aortic vascular remodeling of model rats.Result:1.Compared with normoxia group, the rats of CIH group showed the significant increase of tail mean arterial pressure and the pathological variation of vasculature remodeling by abdominal aorta wall thickening, smaller lumen, increased fibrosis and accumulation of extracellular matrix.Thus pathophysiological rat model of SAS with hypertension was successfully established.2.Related pathomorphism factor of vascular remodeling changes in abdominal vascular tissue.The expression of PCNA,FN and TGF-β1 mRNA increased(P < 0.05 or P < 0.01), while expression of α-SMA reduced significantly(P < 0.05 or P < 0.01).3.Compared with normoxia group, the levels of inflammatory biomarkers including TNF-α、IL-6、IL-10 and hs-CRP in serum of CIH group elevated(P< 0.01). But,serological indexes of hypoxia-intervened group decreased than CIH group(P < 0.05).Moreover, the expression of MCP-1 and MMP-1increased in hypoxia group(P < 0.01), while the expression decreased in hypoxia-intervened group(P <0.05).4.Compared with normoxia group, expression of JNK-1 and MCP-1mRNA and protein in abdominal artery tissue of CIH group were significantly elevated(P < 0.01); But expression of JNK-1 and MCP-1mRNA and protein in hypoxia-intervened group was descent than CIH group(P <0.05 or P<0.01).Conclusion:1.Given certain intermittent hypoxia schedule,the phenomenon that increase blood pressure and abdominal aorta vascular remodeling appears.2.JNK signaling pathway mediates abdominal artery vascular remodeling changes in hypertension induced by SAS rats and affects progression of hypertension secondary to SAS.3.The VR could be reversed by intervension of efficient inhibitors SP600125. Our study provide important targets for further clinical research in developing more effective treatments.