Exogenous spermine alleviates myocardial injury induced by hyperglycemia by inhibiting golgi stress

doi:10.12047/j.cjap.5795.2019.082

Abstract

Abstract: Objective: To investigate whether Golgi stress (GAS) is involved in diabetic cardiomyopathy (DCM) and whether myocardial protection of exogenous spermine is associated with regulation of GAS. Methods: Sixty Wistar rats were randomly divided into normal control group (Control), diabetic group (T1D, STZ 60 mg/kg intraperitoneal injection) and spermine group (T1D+Sp, spermine 5 mg/(kg·d) intraperitoneal injection) for 12 weeks. H9C2 rat cardiomyocytes were randomly divided into control group (Control, 10% FBS-DMEM culture), high glucose group (HG, 10% FBS-DMEM+40 mmol/L glucose) and spermine group (HG+Sp, 10% FBS-DMEM+40 mmol/L glucose+5 μmol/L spermine). Rat serum creatine kinase isoenzyme (CK-MB) and cardiac troponin T (cTnT) were detected by ELISA; Golgi protein GOLPH3, GM130 and Cleaved Caspase3 protein expressions were analyzed using Western blot; immunofluorescence was used to detect GOLPH3 cell localization. Results: In the animal model, compared with the normal group, myocardial ultrastructural damage was obvious,the blood glucose, the serum myocardial enzymes CK-MB and cTnT, the expressions of GOLPH3 and cleaved caspase3 were increased or up-regulated significantly,meanwhile, the body weight,the ejection fraction (EF) and the expression of GM130 were decreased or down-regulated markedly in the diabetic group. In the cell model, similar results were obtained. Immunofluorescence showed stress fragmentation of Golgi apparatus. Exogenous spermine treatment could significantly alleviate the above mentioned damages. Conclusion: Golgi stress occurs in diabetic cardiomyopathy (DCM), and myocardial protection of exogenous spermine is associated with a reduction in Golgi stress (GAS).

Key words: spermine, rat, diabetic cardiomyopathy, Golgi apparatus stress, GOLPH3, GM130

FAN Yu-qi, WANG Yue-hong, SHAO Yi-ying, SHAO Xiao-ting, HU Jing, XU Chang-qing, WEI Can. Exogenous spermine alleviates myocardial injury induced by hyperglycemia by inhibiting golgi stress[J]. CJAP, 2019, 35(5): 385-389.

References

[1] Rossi G. Diagnosis and classification of diabetes mellitus[J]. Recenti Prog Med, 2010, 101 (7-8): 274-276.
[2] Westermeier F, Riquelme JA, Pavez M, et al. New molecular insights of insulin in diabetic cardiomyopathy[J]. Front Physiol, 2016, 7: 125.
[3] Sivasankar D, George M, Sriram DK. Novel approaches in the treatment of diabetic cardiomyopathy[J]. Biomed Pharmacother, 2018, 106: 1039-1045.
[4] Sun X, Chen RC, Yang ZH, et al. Taxifolin prevents diabetic cardiomyopathy in vivo and in vitro by inhibition of oxidative stress and cell apoptosis[J]. Food Chem Toxicol, 2014, 63: 221-232.
[5] Ito Y, Uemura T, Nakano A. Formation and maintenance of the Golgi apparatus in plant cells[J]. Int Rev Cell Mol Bio, 2014, 310: 221-287.
[6] Yang Z, Kirton HM, MacDougall DA, et al. The Golgi apparatus is a functionally distinct Ca2+ store regulated by the PKA and Epac branches of the beta1-adrenergic signaling pathway[J]. Sci Signal, 2015, 8 (398): ra101.
[7] Malik S, deRubio RG, Trembley M, et al. G protein betagamma subunits regulate cardiomyocyte hypertrophy through a perinuclear Golgi phosphatidylinositol 4-phosphate hydrolysis pathway[J]. Mol Biol Cell, 2015, 26 (6): 1188-1198.
[8] Jungk L, Franke H, Salameh A, et al. Golgi fragmentation in human patients with chronic atrial fibrillation: A new aspect of remodeling[J]. Thorac Cardiovasc Surg, 2019, 67(2): 98-106.
[9] 袁迪, 王跃虹, 袁辉, 等. 外源性精胺对缺氧诱导乳鼠心肌细胞凋亡的影响及其机制[J]. 中国应用生理学杂志, 2018, 34 (3): 193-197.
[10]Wei C, Li H, Wang Y, et al. Exogenous spermine inhibits hypoxia/ischemia-induced myocardial apoptosis via regulation of mitochondrial permeability transition pore and associated pathways[J]. Exp Biol Med, 2016, 241(14): 1505-1515.
[11]Fan Y, Zhang C, Li T, et al. A new approach of short wave protection against middle cerebral artery occlusion/reperfusion injury via attenuation of Golgi apparatus stress by inhibition of downregulation of secretory pathway Ca(2+)-ATPase isoform 1 in rats[J]. J Stroke Cerebrovasc Dis, 2016, 25(7): 1813-1822.
[12]李婷. 氧糖剥夺/复氧(OGD/R)模型中GOLPH3介导高尔基体应激(GAS)的相关机制研究[D]. 中南大学, 2013.
[13]Ng MM, Dippold HC, Buschman MD, et al. GOLPH3L antagonizes GOLPH3 to determine Golgi morphology[J]. Mol Biol Cell, 2013, 24 (6): 796-808.
[14]Walker A, Ward C, Sheldrake TA, et al. Golgi fragmentation during Fas-mediated apoptosis is associated with the rapid loss of GM130[J]. Biochem Biophys Res Commun, 2004, 316(1): 6-11.
[15]Li T, You H, Mo X, et al. GOLPH3 mediated Golgi stress response in modulating N2A cell death upon oxygen-glucose deprivation and reoxygenation injury[J]. Mol Neurobiol, 2016, 53(2): 1377-1385.
[16]王艺璐, 刘淼, 尚曼, 等. 心肌缺血预适应循环血中微囊泡对大鼠心肌I/R损伤的作用[J]. 中国应用生理学杂志, 2016, 32 (2): 97-101.
[17]He Y, Yang J, Li H, et al. Exogenous spermine ameliorates high glucose-induced cardiomyocytic apoptosis via decreasing reactive oxygen species accumulation through inhibiting p38/JNK and JAK2 pathways[J]. Int J Clin Exp Pathol, 2015, 8 (12): 15537-15549.
[18]Bai SZ, Sun J, Wu H, et al. Decrease in calcium-sensing receptor in the progress of diabetic cardiomyopathy[J]. Diabetes Res Clin Pract, 2012, 95 (3): 378-385.
[19]Wei C, Wang Y, Li M, et al. Spermine inhibits endoplasmic reticulum stress-induced apoptosis: a new strategy to prevent cardiomyocyte apoptosis[J]. Cell Physiol Biochem, 2016, 38(2): 531-544.