Trimetazidine increases plasma MicroRNA-24 and MicroRNA-126 levels and improves dyslipidemia, inflammation and hypotension in diabetic rats

Document Type : Research article

Authors

1 Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran. Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

2 Departmentof Physiology, Schoolof Medicine, Ahvaz Jundishapur University of MedicalSciences, Ahvaz,Iran.Persian Gulf Physiology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Atherosclerosis Research Center, Ahvaz Jundishapur University of MedicalSciences, Ahvaz,Iran.

3 Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Persian Gulf Physiology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

4 Departmentof Physiology, Schoolof Medicine, Ahvaz Jundishapur University of MedicalSciences, Ahvaz,Iran.Persian Gulf Physiology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

5 Departmentof Physiology, Schoolof Medicine, Ahvaz Jundishapur University of MedicalSciences, Ahvaz,Iran.Persian Gulf Physiology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz,Iran.

Abstract

Trimetazidine (TMZ) improves endothelial dysfunction. However, its beneficial effect on endothelial miRNAs is unexplored in diabetes. The aim of the present study was to evaluate the effects of TMZ on plasma miRNA-24 and miRNA-126, dyslipidemia, inflammation and blood pressure in the diabetic rats. Adult male Sprague-Dawley rats were randomly assigned into four groups (250 ± 20 g, n=8): a control (C), an untreated diabetic (D), a diabetic group administrated with TMZ at 10 mg/kg (T10), and a diabetic group administrated with TMZ at 30 mg/kg (T30) for eight weeks. Diabetes was induced by injection of alloxan (120 mg/kg). The plasma levels of miR-24, miR-126, lipid profile, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), blood glucose, body weight and systolic blood pressure were measured. The diabetic rats showed decreased plasma miR-24, HDL-c (p<0.05), miR-126 (p<0.01), body weight changes percent, body weight, and systolic blood pressure (p<0.001) and increased triglycerides (TG), VLDL-c (p<0.05), TNF-α, total cholesterol (TC) (p<0.01) glucose, MDA and IL-6 (p<0.001). Interestingly, all these changes were significantly improved by TMZ treatment. Our findings propose that TMZ has protective effects on decreased plasma miR-24 and miR-126 levels, inflammation, dyslipidemia and hypotension, and it may participate in endothelial dysfunction and atherosclerosis.

Graphical Abstract

Trimetazidine increases plasma MicroRNA-24 and MicroRNA-126 levels and improves dyslipidemia, inflammation and hypotension in diabetic rats

Keywords

References

( 1) Belardinelli R, Solenghi M, Volpe L and Purcaro A. Trimetazidine improves endothelial dysfunction in chronic heart failure: an antioxidant effect. Eur. Heart. J. (2007) 28: 1102-8.
(2) Lau DC, Dhillon B, Yan H, Szmitko PE and Verma S. Adipokines: molecular links between obesity and atheroslcerosis. Am. J. Physiol. Heart. Circ. Physiol. (2005) 288: 2031-41.
(3) Preis SR, Hwang SJ, Coady S, Pencina MJ, D'Agostino RB Sr, Savage PJ, Levy D and Fox CS. Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005. Circulation (2009) 119: 1728-35.
(4) Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E and Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox. Biol. (2016) 8:199-204.
(5) Wang Y, Meng X and Yan H. Niaspan inhibits diabetic retinopathyinduced vascular inflammation by downregulating the tumor necrosis factoralpha pathway. Mol. Med. Rep. (2017) 15: 1263-71.
(6) Joussen AM, Poulaki V, Le ML, Koizumi K, Esser C, Janicki H, Schraermeyer U, Kociok N, Fauser S, Kirchhof B, Kern TS and Adamis AP. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB. J. (2004) 18: 1450-2.
(7) Friedman RC, Farh KK, Burge CB and Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome. Res. (2009) 19: 92-105.
(8) Ha M and Kim VN. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell. Biol. (2014) 15: 509-24.
(9) Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ and Wang K. The microRNA spectrum in 12 body fluids. Clin. Chem. (2010) 56: 1733-41.
(10) Shantikumar S, Caporali A and Emanueli C. Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc. Res. (2012) 93: 583-93.
(11) Xiang Y. miR-24 in diabetes. Oncotarget. (2015) 6: 16816-7.
(12) Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, Shah A, Willeit J and Mayr M. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ. Res. (2010) 107: 810-7.
(13) Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R and Olson EN. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell. (2008)15: 261-71.
(14) Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, Lorenzen J, Hartmann D, Galuppo P, Kneitz S, Pena JT, Sohn-Lee C, Loyer X, Soutschek J, Brand T, Tuschl T, Heineke J, Martin U, Schulte-Merker S, Ertl G, Engelhardt S, Bauersachs J and Thum T. MicroRNA-24 regulates vascularity after myocardial infarction. Circulation (2011) 124: 720-30.
(15) Yang J, Chen L, Ding J, Fan Z, Li S, Wu H, Zhang J, Yang C, Wang H, Zeng P and Yang J. MicroRNA-24 inhibits high glucose-induced vascular smooth muscle cell proliferation and migration by targeting HMGB1. Gene (2016) 586: 268-73.
(16) Szwed H, Hradec J and Preda I. Anti-ischaemic efficacy and tolerability of trimetazidine administered to patients with angina pectoris: results of three studies. Coron. Artery. Dis. (2001) 12 : 25-8.
(17) Kantor PF, Lucien A, Kozak R and Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res. (2000) 86: 580-8.
(18) Onay-Besikci A, Guner S, Arioglu E, Ozakca I, Ozcelikay AT and Altan VM. The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts. Can. J. Physiol. Pharmacol. (2007) 85: 527-35.
(19) Liu F, Yin L, Zhang L, Liu W, Liu J, Wang Y and Yu B. Trimetazidine improves right ventricular function by increasing miR-21 expression. Int. J. Mol. Med. (2012) 30: 849-55.
(20) Brenner C and Moulin M. Physiological roles of the permeability transition pore. Circ. Res. (2012) 111: 1237-47.
(21) Marchi S, Patergnani S and Pinton P. The endoplasmic reticulum-mitochondria connection: one touch, multiple functions. Biochimica. Et. Biophysica. acta. (2014) 1837: 461-9.
(22) Patergnani S, Suski JM, Agnoletto C, Bononi A, Bonora M, De Marchi E, Giorgi C, Marchi S, Missiroli S, Poletti F, Rimessi A, Duszynski J, Wieckowski MR and Pinton P. Calcium signaling around Mitochondria Associated Membranes (MAMs). Cell. Commun. Signal. (2011) 9: 19.
(23) Park KH, Park WJ, Kim MK, Park DW, Park JH, Kim HS and Cho GY. Effects of trimetazidine on endothelial dysfunction after sheath injury of radial artery. Am. J. Cardiol. (2010) 105: 1723-7.
(24) Xiang YL, He L, Xiao J, Xia S, Deng SB, Xiu Y and She Q. Effect of trimetazidine treatment on the transient outward potassium current of the left ventricular myocytes of rats with streptozotocin-induced type 1 diabetes mellitus. Braz. J. Med. Biol. Res. (2012) 45: 205-11.
(25) Sun X, Zhang M, Sanagawa A, Mori C, Ito S, Iwaki S, Satoh H and Fujii S. Circulating microRNA-126 in patients with coronary artery disease: correlation with LDL cholesterol. Thromb. J. (2012) 10: 16.
(26) Huang X, Gao Y, Qin J and Lu S. The role of miR-34a in the hepatoprotective effect of hydrogen sulfide on ischemia/reperfusion injury in young and old rats. PloS One (2014) 9: 113305.
(27) Salvoza NC, Klinzing DC, Gopez-Cervantes J and Baclig MO. Association of Circulating Serum miR-34a and miR-122 with Dyslipidemia among Patients with Non-Alcoholic Fatty Liver Disease. PloS. One (2016) 11: 0153497.
(28) Bertrand L, Horman S, Beauloye C and Vanoverschelde JL. Insulin signalling in the heart. Cardiovasc. Res. (2008) 79: 238–48.
(29) Osorio-Fuentealba C, Contreras-Ferrat AE, Altamirano F, Espinosa A, Li Q, Niu W, Lavandero S, Klip A and Jaimovich E. Electrical stimuli release ATP to increase GLUT4 translocation and glucose uptake via PI3Kgamma-Akt-AS160 in skeletal muscle cells. Diabetes (2013) 62: 1519–26.
(30) Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes. Dev. (2011) 25: 1895–908.
(31) Lee L, Horowitz J and Frenneaux M. Metabolic manipulation in ischaemic heart disease, a novel approach to treatment. Eur. Heart. J. (2004) 25: 634-41.
(32) Stanley WC and Marzilli M. Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine. Fundam. Clin. Pharmacol. (2003) 17: 133-45.
(33) Fasola TR, Ukwenya B, Oyagbemi AA, Omobowale TO and Ajibade TO. Antidiabetic and antioxidant effects of Croton lobatus L. in alloxan-induced diabetic rats. J. Intercult. Ethnopharmacol. (2016) 5: 364-71.
(34) Hopkins PN. Molecular biology of atherosclerosis. Physiol. Rev. (2013) 93: 1317-542.
(35) Forbes JM and Cooper ME. Mechanisms of diabetic complications. Physiol. Rev. (2013) 93: 137-88.
(36) Tenenbaum A, Klempfner R and Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor. Cardiovasc. Diabetol. (2014) 13: 159.
(37) Galkina E and Ley K. Immune and inflammatory mechanisms of atherosclerosis . Annu. Rev. Immunol. (2009) 27: 165-97.
(38) Ruiz-Meana M. Trimetazidine, oxidative stress, and cell injury during myocardial reperfusion. Revista. Espanola. De. cardiologia. (2005) 58: 895-7.
(39) Monti LD, Setola E, Fragasso G, Camisasca RP, Lucotti P, Galluccio E, Origgi A, Margonato A and Piatti P. Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy. Am. J. Physiol. Endocrinol. Metab. (2006) 290: 54-9.
(40) Goljanek-Whysall K, Iwanejko LA, Vasilaki A, Pekovic-Vaughan V and McDonagh B. Ageing in relation to skeletal muscle dysfunction: redox homoeostasis to regulation of gene expression. Mamm. Genome. (2016) 27: 341-57.
(41) Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY and Srivastava D. miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell (2008) 15: 272-84.
(42) Tao H, Wang MM, Zhang M, Zhang SP, Wang CH, Yuan WJ, Sun T, He LJ and Hu QK. MiR-126 Suppresses the Glucose-Stimulated Proliferation via IRS-2 in INS-1 beta Cells. PLoS. One (2016)11: 0149954.
(43) Li Y, Zhou Q, Pei C, Liu B, Li M, Fang L, Sun Y, Li Y and Meng S. Hyperglycemia and Advanced Glycation End Products Regulate miR-126 Expression in Endothelial Progenitor Cells. J. Vasc. Res. (2016) 53: 94-104. 
(44) Tang ST, Wang F, Shao M, Wang Y and Zhu HQ. MicroRNA-126 suppresses inflammation in endothelial cells under hyperglycemic condition by targeting HMGB1. Vascul. Pharmacol. (2017) 88: 48-55.
(45) Ojwang LO, Banerjee N, Noratto GD, Angel-Morales G, Hachibamba T, Awika JM and Mertens-Talcott SU. Polyphenolic extracts from cowpea (Vigna unguiculata) protect colonic myofibroblasts (CCD18Co cells) from lipopolysaccharide (LPS)-induced inflammation--modulation of microRNA 126. Food. Funct. (2015) 6: 146-54.
(46) Jansen F, Yang XY, Nickenig G and Werner N. Endothelial Microparticle-mediated Transfer of MicroRNA-126 Promotes Vascular Endothelial Cell Repair Via SPRED1 and is Abrogated in Glucose-damaged Endothelial Microparticles. Circulation (2013) 128.pages
(47) Badavi M, Abedi HA, Dianat M and Sarkaki A. Exercise Training and Grape Seed Extract Co-administration Improve Endothelial Dysfunction of Mesenteric Vascular Bed in STZ-induced Diabetic Rats. Int. J. Pharmacol. (2011) 7: 813-20.
(48) Liu IM, Chang CK, Juang SW, Kou DH, Tong YC, Cheng KC and Cheng JT. Role of hyperglycaemia in the pathogenesis of hypotension observed in type-1 diabetic rats. Int. J.Exp. Pathol. (2008) 89: 292-300.
(49) Belardinelli R. Ischemic heart disease and left ventricular dysfunction: the role of trimetazidine. Ital. Heart. J. (2004) 5 : 23S-8S.
(50) Yang J, Fan Z, Yang J, Ding J, Yang C and Chen L. MicroRNA-24 Attenuates Neointimal Hyperplasia in the Diabetic Rat Carotid Artery Injury Model by Inhibiting Wnt4 Signaling Pathway. Int. J. Mol. Sci. (2016) 17. 
Iranian Journal of Pharmaceutical Research
Volume 19, Issue 3
Summer 2020
Pages 248-257

Files

Share

How to cite

Statistics