Öz
Amaç
Diyabetik kardiyomiyopati (DKM), karmaşık patofizyolojik olaylarla karakterizedir. miRNA’lar DKM’de rol oynamaktadır. Çalışmamızda sıçanlarda streptozotosin ile oluşturulan diyabet modelinde miRNA’ların DKM'nin tanı ve tedavisinde biyobelirteç olarak potansiyeli değerlendirildi.
Yöntemler
Bu nedenle, sıçan kalp dokusundan elde edilen miRNA’lar mikroarray ile analiz edildi ve on iki miRNA’nın (rno-miR-200c-3p, rno-miR-129-5p, rno-miR-150-3p, rno-miR-3584-5p, rno-miR-34c-3p, rno-miR-342-3p, rno-miR-466b-3p, rno-miR-466c-3p, rno-miR-31a-3p, rno-miR-15b-5p, rno- miR-196b-3p ve rno-miR-208a-5p) değişen ekspresyon seviyeleri gerçek zamanlı polimeraz zincir reaksiyonu analizi ile doğrulandı.
Bulgular
Doğrulama sonucunda, üç miRNA’nın (rno-miR-15b-5p, rno-miR-196b-3p ve rno-miR-208a-5p) downregüle olduğu ve bir miRNA’nın (rno-miR-200c-3p) upregüle olduğu belirlendi (p<0.05). miR-15b-5p, miR-196b-3p, miR-200c-3p ve miR-208a-5p, DKM’nin düzenlenmesinde yer almakta ve GRAP2 geni, bu miRNA’ların olası hedeflerinden biridir.
Sonuç
miR-200c-3p tanısal değere sahiptir ve biyobelirteç adayı olabilir.
Anahtar Kelimeler: Diyabetik kardiyomiyopati, miRNA ekspresyonu, biyobelirteç, streptozotosin
Kaynakça
Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res. 2018;122:624-38.
Felício JS, Koury CC, Carvalho CT, Abrahão Neto JF, Miléo KB, Arbage TP, et al. Present insights on cardiomyopathy in diabetic patients. Curr Diabetes Rev. 2016;12:384-95.
Jia G, Whaley-Connell A, Sowers JR. Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia. 2018;61:21-8.
Obokata M, Reddy YNV, Borlaug BA. Diastolic dysfunction and heart failure with preserved ejection fraction: understanding mechanisms by using noninvasive methods. JACC Cardiovasc Imaging. 2020;13:245-57.
Ghosh N, Katare R. Molecular mechanism of diabetic cardiomyopathy and modulation of microRNA function by synthetic oligonucleotides. Cardiovasc Diabetol. 2018;17:43.
Ritchie RH, Abel ED. Basic mechanisms of diabetic heart disease. Circ Res. 2020;126:1501-25.
Chandramouli C, Reichelt ME, Curl CL, Varma U, Bienvenu LA, Koutsifeli P, et al. Diastolic dysfunction is more apparent in STZ-induced diabetic female mice, despite less pronounced hyperglycemia. Sci Rep. 2018;8:2346.
Wang S, Ding L, Ji H, Xu Z, Liu Q, Zheng Y. The role of p38 MAPK in the development of diabetic cardiomyopathy. Int J Mol Sci. 2016;17:1037.
Watanabe K, Thandavarayan RA, Harima M, Sari FR, Gurusamy N, Veeraveedu PT, et al. Role of differential signal-ing pathways and oxidative stress in diabetic cardiomyopathy. Curr Cardiol Rev. 2010;6:280-90.
Silva DCPD, Carneiro FD, Almeida KC, Fernandes-Santos C. Role of miRNAs on the pathophysiology of cardiovascular diseases. Arq Bras Cardiol. 2018;111:738-46.
O'Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne). 2018;9:402.
Zhang S, Weinheimer C, Courtois M, Kovacs A, Zhang CE, Cheng AM, et al. The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. J Clin Invest. 2003;111:833-41.
Manu MS, Rachana KS, Advirao GM. Altered expression of IRS2 and GRB2 in demyelination of peripheral neurons: Implications in diabetic neuropathy. Neuropeptides. 2017;62:71-9.
Akbarzadeh A, Norouzian D, Mehrabi MR, Jamshidi SH, Farhangi A, Allah Verdi A, et al. Induction of diabetes by streptozotocin in rats. Indian J Clin Biochem. 2007;22:60-4.
Masè M, Grasso M, Avogaro L, D'Amato E, Tessarolo F, Graffigna A, et al. Selection of reference genes is critical for miRNA expression analysis in human cardiac tissue. A focus on atrial fibrillation. Sci Rep. 2017;7:41127.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402-8.
Kiernan JA. Histological and histochemical methods:theory and practice, 3rd edition. Shock. 1999;12:479.
Fabregat A, Korninger F, Viteri G, Sidiropoulos K, Marin-Garcia P, Ping P, et al. Reactome graph database: Efficient access to complex pathway data. PLoS Comput Biol. 2018;14:e1005968.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37(Suppl 1):81-90.
Sherwani SI, Khan HA, Ekhzaimy A, Masood A, Sakharkar MK. Significance of HbA1c test in diagnosis and prognosis of diabetic patients. Biomark Insights. 2016;11:95-104.
Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab. 2016;20:546-51.
Öztürk Z. Diabetes, oxidative stress and endothelial dysfunction. Bezmialem Science. 2019;7:52-7.
Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018;17:83.
Huang ZP, Neppl RL, Wang DZ. MicroRNAs in cardiac remodeling and disease. J Cardiovasc Transl Res. 2010;3:212-8.
Felekkis K, Papaneophytou C. Challenges in using circulating biomarkers for cardiovascular diseases. Int J Mol Sci. 2020;21:561.
Mir R, Elfaki I, Khullar N, Waza AA, Jha C, Mir MM, et al. Role of selected miRNAs as diagnostic and prognostic biomarkers in cardiovascular diseases, including coronary artery disease, myocardial infarction and atherosclerosis. J Cardiovasc Dev Dis. 2021;8:22.
Singh GB, Raut SK, Khanna S, Kumar A, Sharma S, Prasad R, et al. MicroRNA-200c modulates DUSP-1 expression in diabetes-induced cardiac hypertrophy. Mol Cell Biochem. 2017;424:1-11.
Chen Z, Zhang S, Guo C, Li J, Sang W. Downregulation of miR-200c protects cardiomyocytes from hypoxia-induced apoptosis by targeting GATA-4. Int J Mol Med. 2017;39:1589-96.
Wang W, Yang C, Wang XY, Zhou LY, Lao GJ, Liu D, et al. MicroRNA-129 and -335 promote diabetic wound healing by Inhibiting Sp1-Mediated MMP-9 expression. Diabetes. 2018;67:1627-38.
Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 2007;116:258-67.
Sun G, Hu H, Tian X, Yue J, Yu H, Yang X, et al. Identification and analysis of microRNAs in the left ventricular myocardium of two-kidney one-clip hypertensive rats. Mol Med Rep. 2013;8:339-44.
Yang Y, Li R, Cao Y, Dai S, Luo S, Guo Q, et al. Plasma MIR-212-3p as a biomarker for acute right heart failure with pulmonary artery hypertension. Ann Transl Med. 2020;8:1571.
Dahlmans D, Houzelle A, Andreux P, Jörgensen JA, Wang X, de Windt LJ, et al. An unbiased silencing screen in muscle cells identifies miR-320a, miR-150, miR-196b, and miR-34c as regulators of skeletal muscle mitochondrial metabolism. Mol Metab. 2017;6:1429-42.
Bernardo BC, Gao XM, Tham YK, Kiriazis H, Winbanks CE, Ooi JY, et al. Silencing of miR-34a attenuates cardiac dysfunction in a setting of moderate, but not severe, hypertrophic cardiomyopathy. PLoS One. 2014;9:e90337.
Zheng M, Wang M. A narrative review of the roles of the miR-15/107 family in heart disease: lessons and prospects for heart disease. Ann Transl Med. 2021;9:66.
Gu W, Xu Y, Xie X, Wang T, Ko JH, Zhou T. The role of RNA structure at 5' untranslated region in microRNA-mediated gene regulation. RNA. 2014;20:1369-75.
Peter ME. Targeting of mRNAs by multiple miRNAs: the next step. Oncogene. 2010;29:2161-4.
Niyazova R, Atambayeva Sh, Akimniyazova A, Pinsky I, Alybaeva A, Faye B, et al. Features of mir-466-3p binding sites in mRNA genes with different functions. Int J Biol Chem. 2015;8:44-51.
Xiao J, Liu H, Cretoiu D, Toader DO, Suciu N, Shi J, et al. miR-31a-5p promotes postnatal cardiomyocyte proliferation by targeting RhoBTB1. Exp Mol Med. 2017;49:e386.
Reilly SN, Liu X, Carnicer R, Recalde A, Muszkiewicz A, Jayaram R, et al. Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase. Sci Transl Med. 2016;8:340-74.
Ellis KL, Cameron VA, Troughton RW, Frampton CM, Ellmers LJ, Richards AM. Circulating microRNAs as candidate markers to distinguish heart failure in breathless patients. Eur J Heart Fail. 2013;15:1138-47.
van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science. 2007;316:575-9.
Jaffe AS, Ravkilde J, Roberts R, Naslund U, Apple FS, Galvani M. It’s time for a change to a troponin standard. Circulation. 2000;102:1216-20.
Ji X, Takahashi R, Hiura Y, Hirokawa G, Fukushima Y, Iwai N. Plasma miR-208 as a biomarker of myocardial injury. Clin Chem. 2009;55:1944-9.
Duan Y, Zhou B, Su H, Liu Y, Du C. miR-150 regulates high glucose-induced cardiomyocyte hypertrophy by targeting the transcriptional co-activator p300. Exp Cell Res. 2013;319:173-84.
Feng B, Chen S, George B, Feng Q, Chakrabarti S. miR133a regulates cardiomyocyte hypertrophy in diabetes. Diabetes Metab Res Rev. 2010;26:40-9.
Kuwabara Y, Horie T, Baba O, Watanabe S, Nishiga M, Usami S, et al. MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway. Circ Res. 2015;116:279-88.
Raut SK, Kumar A, Singh GB, Nahar U, Sharma V, Mittal A, et al. miR-30c mediates upregulation of Cdc42 and Pak1 in diabetic cardiomyopathy. Cardiovasc Ther. 2015;33:89-97.
Shen E, Diao X, Wang X, Chen R, Hu B. MicroRNAs involved in the mitogen-activated protein kinase cascades pathway during glucose-induced cardiomyocyte hypertrophy. Am J Pathol. 2011;179:639-50.
Yan B, Ren J, Zhang Q, Gao R, Zhao F, Wu J, et al. Antioxidative effects of natural products on diabetic cardiomyopathy. J Diabetes Res. 2017;2017:2070178.
Cai F. [Studies of enzyme histochemistry and ultrastructure of the myocardium in rats with streptozotocin-induced diabetes]. Zhonghua Yi Xue Za Zhi. 1989;69:276-8.
Miller MA, Zavhary JF. Mechanisms and morphology of cellular injury, adaptation, and death. Pathologic Basis of Veterinary Disease. 2017:2-43.
Zhang J, Qiu H, Huang J, Ding S, Huang B, Wu Q, et al. Establishment of a diabetic myocardial hypertrophy model in Mus musculus castaneus mouse. Int J Exp Pathol. 2018;99:295-303.
Witkos TM, Koscianska E, Krzyzosiak WJ. Practical aspects of microRNA target prediction. Curr Mol Med. 2011;11:93-109.
Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat Rev Cardiol. 2020;17:585-607.
