Chronic Intermittent Hypobaric Hypoxia Improves Iron Metabolism Disorders By IL-6/JAK2/STAT3 And EPO/STAT5/ERFE Signaling Pathway In Metabolic Syndrome Rats

Objective: Our previous study demonstrated that chronic intermittent hypobaric hypoxia(CIHH)can improve iron metabolism disorder in obese rats through the down-regulation of hepcidin by decreasing interleukin-6(IL-6)and increasing erythropoietin(EPO).This study aimed to observe the molecular mechanism of CIHH in improving iron metabolismdisorders,especially by Janus kinase/signal transducer and activation of transcription(JAK/STAT)signaling pathway in metabolic syndrome(MS)rats.Methods: 6-7 weeks old male Sprague-Dawlay rats were randomly divided into four groups: CON(fed with chow diet and drinking water),CIHH(treated with hypobaric hypoxia simulating 5000-m altitude for 28 days,6h daily),MS(16-week MS inducement with high fat diet and10% fructose water),MS+CIHH(CIHH treatment following week MS inducement).The serum level of fasting glucose and lipid metabolism,IL-6 and EPO was measured.The protein expression of JAK2,STAT3 and STAT5 was examined.The mRNA expression of erythroferrone(ERFE)and hepcidin was analyzed.Results:1.Compared with CON rats,fasting blood glucose,total cholesterol,triglycerides and low-density lipoprotein were significantly increased in MS rats(P<0.05),there was no significant difference in the above indexes in CIHH rats and the biochemical indexes of MS+CIHH rats have been significantly reduced compared with MS rats(P<0.05).2.Compared with CON rats,MS rats have significantly increased IL-6 and significantly decreased EPO(P<0.05).but IL-6 level and EPO level in CIHH rats did not differ significantly(P>0.05).After MS rats were treated with CIHH,the level of IL-6 decreased significantly,and the level of EPO increased(P<0.05).3.Compared with CON rats,the expression of JAK2 and STAT3 proteins in the liver of MS rats was significantly increased(P<0.05),and there was no significant difference in CIHH rats(P>0.05).The expres-sion level of JAK2 and STAT3 proteins was significantly reduced after CIHH treatment(P<0.05).4.Compared with CON rats,the expression of STAT5 protein and ERFE mRNA in the spleen of MS rats was significantly reduced(P<0.05),and there was no significant difference in CIHH rats(P>0.05).Theexpression levels of STAT5 protein and ERFE mRNA were significantlyelevated after CIHH treatment(P<0.05).5.Compared with CON rats,the relative expression of hepcidin mRNA in the liver of MS rats was significantly increased(P<0.05),and there was no significant change in CIHH rats(P>0.05).Relative expression of hepcidin mRNA was significantly reduced in CIHH-treated MS rats(P<0.05).Conclusions:CIHH improved iron metabolism disorders possibly through inhibiting IL-6/JAK2/STAT3 and activating the EPO/STAT5/ERFE signaling pathway,thus down-regulating hepcidin in MS rats.