1,25(OH)_2D_3调控内质网稳态改善自发性糖尿病大鼠心肌损伤
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摘要
目的探讨1, 25(OH)_2D_3补充改善ZDF大鼠心肌损伤的潜在机制。方法健康雄性5～6 w龄Zucker瘦型鼠为正常对照组(C),胖型鼠按照体质量随机分为模型组(DM)、1, 25(OH)_2D_3低(DM+VD(L))、VD中(DM+VD(M))、高(DM+VD(H))剂量干预共4组。各组大鼠喂养至12 w龄,检测血糖血脂、心脏损伤及心肌细胞内质网应激相关指标。结果 DM组血脂、血糖显著升高,心肌出现严重损伤,内质网应激/未折叠蛋白反应标志蛋白GPR78显著降低,IRE1α-XBP1通路受阻;不同剂量1, 25(OH)_2D_3干预对ZDF大鼠血脂血糖及心肌损伤均有改善,其中、高剂量改善作用更为显著。1,25(OH)_2D_3低剂量干预未能显著改善ZDF大鼠未折叠蛋白反应的失活,1,25(OH)_2D_3中高剂量干预激活IRE1α-XBP1通路恢复内质网的稳态调节,中剂量的改善作用优于高剂量。结论适量的1,25(OH)_2D_3可通过IRE1α-XBP1通路调节内质网稳态,从而减轻糖尿病心肌损伤。[营养学报,2019,41(1):58-62]
Objective To investigate the potential protection of 1, 25(OH)_2D_3 on type 2 diabetes mellitus induced myocardial damage. Methods Male Zucker lean rats(5-6 weeks) were assigned to control group(C). Male Zucker fatty rats(5-6 weeks) were randomly divided into 4 groups according to their body weight: T2 DM group(DM), low dose 1, 25(OH)_2D_3 group supplementation(DM+VD(L)), middle dose 1, 25(OH)_2D_3 group(DM+VD(M)), high dose 1, 25(OH)_2D_3 group(DM+VD(H)); All the rats were fed to 12 weeks of age. Serum glucose, heart injury and endoplasmic reticulum stress/unfolded protein response were measured. Results Compared with the control, serum glucose and TC of DM group rats were increased, and the cardiomyocytes were damaged, GRP78 was decreased and the IRE1α-XBP1 pathway was blocked.1, 25(OH)_2D_3 supplementations decreased serum glucose and alleviated myocardial injury, in which the middle and high doses of 1, 25(OH)_2D_3 supplementation were more effective. The middle and high doses of 1, 25(OH)_2D_3 intervention activated IRE1α-XBP1 pathway to restore endoplasmic reticulum homeostasis, and the improvement effect of middle dose was better than that of high dose. Conclusion Appropriate amount of 1, 25(OH)_2D_3 supplementation may attenuate diabetic myocardial injury by regulating endoplasmic reticulum homeostasis through activating IRE1α-XBP1 pathway. [ACTA NUTRIMENTA SINICA, 2019, 41(1):58-62]
Objective To investigate the potential protection of 1, 25(OH)_2D_3 on type 2 diabetes mellitus induced myocardial damage. Methods Male Zucker lean rats(5-6 weeks) were assigned to control group(C). Male Zucker fatty rats(5-6 weeks) were randomly divided into 4 groups according to their body weight: T2 DM group(DM), low dose 1, 25(OH)_2D_3 group supplementation(DM+VD(L)), middle dose 1, 25(OH)_2D_3 group(DM+VD(M)), high dose 1, 25(OH)_2D_3 group(DM+VD(H)); All the rats were fed to 12 weeks of age. Serum glucose, heart injury and endoplasmic reticulum stress/unfolded protein response were measured. Results Compared with the control, serum glucose and TC of DM group rats were increased, and the cardiomyocytes were damaged, GRP78 was decreased and the IRE1α-XBP1 pathway was blocked.1, 25(OH)_2D_3 supplementations decreased serum glucose and alleviated myocardial injury, in which the middle and high doses of 1, 25(OH)_2D_3 supplementation were more effective. The middle and high doses of 1, 25(OH)_2D_3 intervention activated IRE1α-XBP1 pathway to restore endoplasmic reticulum homeostasis, and the improvement effect of middle dose was better than that of high dose. Conclusion Appropriate amount of 1, 25(OH)_2D_3 supplementation may attenuate diabetic myocardial injury by regulating endoplasmic reticulum homeostasis through activating IRE1α-XBP1 pathway. [ACTA NUTRIMENTA SINICA, 2019, 41(1):58-62]
引文
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[16]杨竞霄,陈静园,王子宽.大鼠心肌组织内质网应激因子GRP78及caspase-12的表达及其对心脏结构和功能的影响[J].山西医科大学学报,2016,47:679-684.
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[18]Gardner BM,Walter P.Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response[J].Science,2011,333:1891-1894.
[19]Chen Y,Brandizzi F.IRE1:ER stress sensor and cell fate executor[J].Trends Cell Biol,2013,23:547-555.
[20]Margariti A,Li H,Chen T,et al.XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation[J].J Biol Chem,2013,288:859-872.
[21]Cui W,Ma J,Wang X,et al.Free fatty acid induces endoplasmic reticulum stress and apoptosis ofβ-cells by Ca2+/calpain-2 pathways[J].PLoS One,2013,8:e59921.
[2]Bugger H,Abel ED.Molecular mechanisms of diabetic cardiomyopathy[J].Diabetologia,2014,57:660-671.
[3]Yang L,Zhao D,Ren J,et al.Endoplasmic reticulum stress and protein quality control in diabetic cardiomyopathy[J].Biochim Biophys Acta,2015,1852:209-218.
[4]Bhat TA,Chaudhary AK,Kumar S,et al.Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer[J].Biochim Biophys Acta,2017,1867:58-66.
[5]Van Belle TL,Gysemans C,Mathieu C.Vitamin D and diabetes:the odd couple[J].Trends Endocrinol Metab,2013,24:561-568.
[6]Riek AE,Oh J,Sprague JE,et al.Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients[J].J Biol Chem,2012,287:38482-38494.
[7]Lee TW,Lee TI,Chang CJ,et al.Potential of vitamin D in treating diabetic cardiomyopathy[J].Nutr Res,2015,35:269-279.
[8]Wei H,Qu H,Wang H,et al.1,25-Dihydroxyvitamin-D3prevents the development of diabetic cardiomyopathy in type 1 diabetic rats by enhancing autophagy via inhibiting theβ-catenin/TCF4/GSK-3β/mTOR pathway[J].J Steroid Biochem Mol Biol,2017,168:71-90.
[9]Li YX,Zhou L.Vitamin D deficiency,obesity and diabetes[J].Cell MolBiol(Noisy-le-grand),2015,61:35-38.
[10]Zeng X,Yu X,Xiao S,et al.Effects of 1,25-dihydroxyvitamin D3 on pathological changes in rats with diabetic cardiomyopathy[J].Lipids Health Dis,2017,16:109.
[11]Shiota M,Printz RL.Diabetes in Zucker diabetic fatty rat[J].Methods Mol Biol,2012:913:103-123.
[12]宋丹,冉丽媛,姜如娇,等.糖尿病研究中的动物模型进展[J].中国比较医学杂志,2016,26:83-87.
[13]Yang Q,Gao H,Dong R,et al.Sequential changes of endoplasmicreticulum stress and apoptosis in myocardial fibrosis of diabetes mellitus-induced rats[J].Mol Med Rep,2016,13:5037-5044.
[14]Oakes SA,Papa FR.The role of endoplasmic reticulum stress in human pathology[J].Annu Rev Pathol,2015,10:173-194.
[15]Byrne CD,Targher G.Ectopic fat,insulin resistance,and nonalcoholic fatty liver disease:implication for cardiovascular disease[J].Arterioscl Thromb Vasc Biol,2014,34:1155-1161.
[16]杨竞霄,陈静园,王子宽.大鼠心肌组织内质网应激因子GRP78及caspase-12的表达及其对心脏结构和功能的影响[J].山西医科大学学报,2016,47:679-684.
[17]Zhang Q,Li Y,Liang T,et al.ER stress and autophagy dysfunction contribute to fatty liver in diabetic mice[J].Int J Biol sci,2015,11:559-568.
[18]Gardner BM,Walter P.Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response[J].Science,2011,333:1891-1894.
[19]Chen Y,Brandizzi F.IRE1:ER stress sensor and cell fate executor[J].Trends Cell Biol,2013,23:547-555.
[20]Margariti A,Li H,Chen T,et al.XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation[J].J Biol Chem,2013,288:859-872.
[21]Cui W,Ma J,Wang X,et al.Free fatty acid induces endoplasmic reticulum stress and apoptosis ofβ-cells by Ca2+/calpain-2 pathways[J].PLoS One,2013,8:e59921.