| Background:Atrial fibrillation often coexists with various chronic diseases,such as diabetes,hypertension,etc.Diabetes is a systemic chronic metabolic disease,an independent risk factor for atrial fibrillation,but its specific mechanism needs to be studied.Endoplasmic reticulum associated with organelles domains are involved in the occurrence and development of various chronic metabolic diseases in recent studies.The IP3R1/GRP75/VDAC1 complex and mitochondria related calcium channels in the ER-mitochondria communication structure jointly regulate intracellular calcium balance and mitochondria calcium concentration,and mitochondria calcium is the key to cell survival.Therefore,this study guided by the interdisciplinary study of diabetic atrial fibrillation and focusing on the interaction of organelles,and we proposed a hypothesis that ERS causes ER-mitochondria calcium flow disorder and induces apoptosis,leads to the pathogenesis of atrial remodeling in diabetes rats.Purpose: 1):To explore whether ERS is involved in atrial remodeling in diabetes;2): To investigate the effect of IP3R1/GRP75/VDAC1 complex and mitochondria related calcium channels on the atrial remodeling in diabetic rats and its molecular mechanism;3):To explore the effect ERS inhibition on atrial ER-mitochondria calcium flow in diabetic rats and its intervention in atrial remodeling.Methods Part 1 First,we verified tunicamycin(TN)-induced rats atrial remodeling by establishing TN-induced ERS rats.The rats were divided into control,diabetes and 4PBA group.Part 2 Feeding with high fat and tail vein injecting 30mg/kg streptozotocin to establish type 2 diabetes.The rats were divided into control,diabetes and 4PBA group.The 4PBA group was given ERS inhibitor 4-PBA(4-phenylbutyric acid)by gavage in diabetic rats at a dose of 20mg/kg/d for 8 weeks.Blood glucose,OGTT and insulin were detected.Detecting atrial tissue ERS markers GRP78,CHOP,and XBP1.Part 3 1)Ultrasound for LAD and cardiac function;2)Hemodynamics for cardiac function;3)Pathological experiment for cross-sectional area of atrial myocytes and the level of left atrial fibrosis;4)Electrophysiological experiment and electrical mapping for atrial fibrillation induction rate,the atrial surface conduction velocity and heterogeneity index.Part 4 1)Western Blot analysis for GRP75,VDAC1,MCU,BCL,BAX and other proteins;2)Mitochondria calcium ion detection.Results 1)The obvious symptoms in diabetic group.The blood glucose were maintained at 16.7mmol/L at random during the whole experiment;2)The TN-induced rats showed significant fibrosis compared with control group,while 4PBA could significantly reduce the degree of fibrosis.ERS marker of GRP78 and CHOP were significantly increased in diabetes group,GRP78 and CHOP were decreased in 4PBA group;3)The LAD,myocardial cell cross-sectional area,atrial fibrosis,atrial fibrillation induction rate and conduction heterogeneity index in the diabetic group were increased compared with control group,and 4PBA could alleviate the above changes;4)GRP75,VDAC1 and MCU were increased in the diabetic group,4PBA reduced the expression of MCU.The protein BAX and protein bcl-2 of bcl2 family were increased,and 4PBA could reduce expression of both.Compared with the control group,the mitochondria calcium in the diabetic group decreased significantly,while the mitochondria calcium in the 4PBA group increased.Conclusions 1)ERS is one of the mechanisms of atrial remodeling in diabetes;2)ER-mitochondria calcium flow participates in atrial remodeling in diabetes rats by affecting the balance of mitochondria calcium;3)Inhabiting ERS can improve the atrial mitochondria calcium storage capacity and atrial remodeling in diabetic rats. |
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