Role And Mechanism Of Endoplasmic Reticulum Stress And Autophagy In Myocardial Injury Caused By OSAHS With Obesity

Objective:In this study,a mouse model of Chronic Intermittent Hypoxia(CIH)with High fat Diet(HFD)causing myocardial injury was successfully established.Aim to simulate the pathophysiological conditions of patients with Obstructive Sleep Apnea Hypopnea Syndrome(OSAHS)and obesity.It’s aim was to further verify the effects of CIH combined with HFD on the cardiac function of mice,and to further explore the potential mechanisms of ERS and autophagy in the myocardial injury caused by OSAHS combined with obesity.Methods:1.CIH and HFD mouse models were established.C57/BL6 mice were divided into four groups:Control group(RC group),Chronic intermittent hypoxia group(RH group),High fat diet group(HC group),Chronic intermittent hypoxia + High fat diet group(HH group);2.The body weight and heart weight of mice were measured.The different changes of heart structure and function in each group were detected by ultrasonic cardiogram(UCG);3.Hematoxylin-eosin(HE)staining was performed to observe the pathological changes of heart tissue of mice in each group;The activity of serum creatine kinase(CK)and lactate dehydrogenase(LDH)in each group was analyzed by biochemical analysis;The expression of apoptotic protein Caspase3 in myocardial tissue of mice in each group was detected by Western Blot;RT-PCR was used to detect the m RNA expression of inflammatory factors in heart tissues of mice in different treatment groups;4.The m RNA and protein expressions of ER stress genes in heart tissues of mice in different treatment groups were detected by RT-PCR and Western Blot(WB);The m RNA and protein expressions of autophagy in heart tissues were detected by RT-PCR and Western Blot.Results:1.It was found that after the modeling of CIH and HFD,the body weight of mice treated with HFD alone increased most significantly compared with the control group while CIH alone decreased body weight most significantly.The body weight of mice in the CIH+HFD treatment group was significantly higher than that in the CIH alone group,and there was no significant statistical difference between the control group and the HFD alone group;Cardiac ultrasonography showed that ventricular muscle thickened significantly in mice treated with CIH+HFD compared with the control group,and myocardial systolic and diastolic functions decreased significantly.While ventricular muscle thickened slightly in mice treated with CIH or HFD alone compared with the control group,but there was no significant change in cardiac function.;2.He staining showed that the myocardial structure of mice in the CIH+HFD treatment group was obviously disordered and the myocardial cell swelling was obvious,while the mice in the CIH or HFD alone had slight changes compared with the control group;Serum biochemical tests showed that the expressions of creatine kinase(CK)and lactate dehydrogenase(LDH)in serum of mice treated with CIH+HFD were significantly higher than those in the control group,indicating the most serious myocardial injury,while those in only the CIH or HFD group were slightly higher than those in the control group;Similarly,the increase of apoptotic protein Caspase3 in CIH+HFD group was the most significant compared with other groups;CIH+HFD treatment also significantly upregulated the m RNA expression of inflammatory cytokines IL-6,TNF-α and TGF-β;3.The expression of ER stress-related genes in different treatment groups was further detected.Both RT-PCR and WB indicated that the expression of ER stress-related genes such as CHOP,x BP1 s and IRE1α were significantly increased in CIH+HFD treatment group;RTPCR and WB results also showed that the m RNA expressions of autophagy-related genes LC3-II,Beclin1,Parkin,Bnip3,Atg5,FUNDC1 in the CIH+HFD treatment group were significantly up-regulated compared with RC group,and the protein expressions of LC3-II,Beclin1 and Bnip3 were similar.Conclusion:In this study,CIH and HFD models were successfully established in mice,and it was found that CIH+HFD treatment led to the most significant cardiac injury in mice.Further detection revealed that ER stress and autophagy related gene expression increased,suggesting that ER stress and autophagy may play a regulatory role in the severe myocardial injury caused by CIH combined with high fat diet.