Therapeutic overexpression of miR-92a-2-5p ameliorated cardiomyocyte oxidative stress injury in the development of diabetic cardiomyopathy
Tóm tắt
Diabetic cardiomyopathy (DCM) results from pathological changes in cardiac structure and function caused by diabetes. Excessive oxidative stress is an important feature of DCM pathogenesis. MicroRNAs (miRNAs) are key regulators of oxidative stress in the cardiovascular system. In the present study, we screened for the expression of oxidative stress-responsive miRNAs in the development of DCM. Furthermore, we aimed to explore the mechanism and therapeutic potential of miR-92a-2-5p in preventing diabetes-induced myocardial damage. An experimental type 2 diabetic (T2DM) rat model was induced using a high-fat diet and low-dose streptozotocin (30 mg/kg). Oxidative stress injury in cardiomyocytes was induced by high glucose (33 mmol/L). Oxidative stress-responsive miRNAs were screened by quantitative real-time PCR. Intervention with miR-92a-2-5p was accomplished by tail vein injection of agomiR in vivo or adenovirus transfection in vitro. The expression of miR-92a-2-5p in the heart tissues was significantly decreased in the T2DM group. Decreased miR-92a-2-5p expression was also detected in high glucose-stimulated cardiomyocytes. Overexpression of miR-92a-2-5p attenuated cardiomyocyte oxidative stress injury, as demonstrated by increased glutathione level, and reduced reactive oxygen species accumulation, malondialdehyde and apoptosis levels. MAPK interacting serine/threonine kinase 2 (MKNK2) was verified as a novel target of miR-92a-2-5p. Overexpression of miR-92a-2-5p in cardiomyocytes significantly inhibited MKNK2 expression, leading to decreased phosphorylation of p38-MAPK signaling, which, in turn, ameliorated cardiomyocyte oxidative stress injury. Additionally, diabetes-induced myocardial damage was significantly alleviated by the injection of miR-92a-2-5p agomiR, which manifested as a significant improvement in myocardial remodeling and function. miR-92a-2-5p plays an important role in cardiac oxidative stress, and may serve as a therapeutic target in DCM.
Tài liệu tham khảo
Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972;30(6):595–602.
Lorenzo-Almoros A, Tunon J, Orejas M, Cortes M, Egido J, Lorenzo O. Diagnostic approaches for diabetic cardiomyopathy. Cardiovasc Diabetol. 2017;16(1):28.
Jia G, Whaley-Connell A, Sowers JR. Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia. 2018;61(1):21–8.
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103(2):137–49.
Kiencke S, Handschin R, von Dahlen R, Muser J, Brunner-Larocca HP, Schumann J, et al. Pre-clinical diabetic cardiomyopathy: prevalence, screening, and outcome. Eur J Heart Fail. 2010;12(9):951–7.
Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail. 2015;3(2):136–45.
Kristensen SL, Mogensen UM, Jhund PS, Petrie MC, Preiss D, Win S, et al. Clinical and Echocardiographic Characteristics and Cardiovascular Outcomes According to Diabetes Status in Patients With Heart Failure and Preserved Ejection Fraction: A Report From the I-Preserve Trial (Irbesartan in Heart Failure With Preserved Ejection Fraction). Circulation. 2017;135(8):724–35.
Palomer X, Pizarro-Delgado J, Vazquez-Carrera M. Emerging actors in diabetic cardiomyopathy: heartbreaker biomarkers or therapeutic targets? Trends Pharmacol Sci. 2018;39(5):452–67.
Matsuzaki S, Eyster C, Newhardt MF, Giorgione JR, Kinter C, Young ZT, et al. Insulin signaling alters antioxidant capacity in the diabetic heart. Redox Biol. 2021;47: 102140.
Haghani K, Bakhtiyari S, Doost MJ. Alterations in plasma glucose and cardiac antioxidant enzymes activity in streptozotocin-induced diabetic rats: effects of trigonella foenum-graecum extract and swimming training. Can J Diabetes. 2016;40(2):135–42.
Wilson AJ, Gill EK, Abudalo RA, Edgar KS, Watson CJ, Grieve DJ. Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting. Heart. 2018;104(4):293–9.
Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014;57(4):660–71.
Moreli JB, Santos JH, Rocha CR, Damasceno DC, Morceli G, Rudge MV, et al. DNA damage and its cellular response in mother and fetus exposed to hyperglycemic environment. Biomed Res Int. 2014;2014: 676758.
Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J, et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J. 2010;31(6):659–66.
Letafati A, Najafi S, Mottahedi M, Karimzadeh M, Shahini A, Garousi S, et al. MicroRNA let-7 and viral infections: focus on mechanisms of action. Cell Mol Biol Lett. 2022;27(1):14.
Kansakar U, Varzideh F, Mone P, Jankauskas SS, Santulli G. Functional Role of microRNAs in Regulating Cardiomyocyte Death. Cells. 2022;11(6):983.
Yang F, Liu S, Gu Y, Yan Y, Ding X, Zou L, et al. MicroRNA-22 promoted osteogenic differentiation of valvular interstitial cells by inhibiting CAB39 expression during aortic valve calcification. Cell Mol Life Sci. 2022;79(3):146.
Raso A, Dirkx E, Sampaio-Pinto V, El Azzouzi H, Cubero RJ, Sorensen DW, et al. A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration. Nat Commun. 2021;12(1):4808.
Wiedmann F, Kraft M, Kallenberger S, Büscher A, Paasche A, Blochberger PL, et al. MicroRNAs Regulate TASK-1 and Are Linked to Myocardial Dilatation in Atrial Fibrillation. J Am Heart Assoc. 2022;89:e023472.
Gong YY, Luo JY, Wang L, Huang Y. MicroRNAs Regulating Reactive Oxygen Species in Cardiovascular Diseases. Antioxid Redox Signal. 2018;29(11):1092–107.
Kura B, Szeiffova Bacova B, Kalocayova B, Sykora M, Slezak J. Oxidative Stress-Responsive MicroRNAs in Heart Injury. Int J Mol Sci. 2020;21(1):358.
Gupta SK, Foinquinos A, Thum S, Remke J, Zimmer K, Bauters C, et al. Preclinical development of a MicroRNA-based therapy for elderly patients with myocardial infarction. J Am Coll Cardiol. 2016;68(14):1557–71.
Shao Q, Meng L, Lee S, Tse G, Gong M, Zhang Z, et al. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats. Cardiovasc Diabetol. 2019;18(1):165.
Ding X, Yan Y, Zhang C, Xu X, Yang F, Liu Y, et al. OCT4 regulated neointimal formation in injured mouse arteries by matrix metalloproteinase 2-mediated smooth muscle cells proliferation and migration. J Cell Physiol. 2021;236(7):5421–31.
Gu Y, Yang F, Yu YC, Meng JX, Li Y, Xu RM, et al. Microarray analysis and functional characterization revealed NEDD4-mediated cardiomyocyte autophagy induced by angiotensin II. Cell Stress Chaperon. 2019;24(1):203–12.
Chen Y, Wang X. miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res. 2020;48(D1):D127–31.
McGeary SE, Lin KS, Shi CY, Pham TM, Bisaria N, Kelley GM, et al. The biochemical basis of microRNA targeting efficacy. Science. 2019;366(6472):e1741.
Rehmsmeier M, Steffen P, Hochsmann M, Giegerich R. Fast and effective prediction of microRNA/target duplexes. RNA. 2004;10(10):1507–17.
Caggiano R, Cattaneo F, Moltedo O, Esposito G, Perrino C, Trimarco B, et al. miR-128 is implicated in stress responses by targeting MAFG in Skeletal Muscle Cells. Oxid Med Cell Longev. 2017;2017:9308310.
Gou L, Zhao L, Song W, Wang L, Liu J, Zhang H, et al. Inhibition of miR-92a suppresses oxidative stress and improves endothelial function by upregulating heme oxygenase-1 in db/db Mice. Antioxid Redox Signal. 2018;28(5):358–70.
Xiao Y, Zhang Y, Chen Y, Li J, Zhang Z, Sun Y, et al. Inhibition of MicroRNA-9-5p protects against cardiac remodeling following myocardial infarction in mice. Hum Gene Ther. 2019;30(3):286–301.
Tong Z, Tang Y, Jiang B, Wu Y, Liu Y, Li Y, et al. Phosphorylation of nucleolin is indispensable to upregulate miR-21 and inhibit apoptosis in cardiomyocytes. J Cell Physiol. 2019;234(4):4044–53.
Costantino S, Paneni F, Luscher TF, Cosentino F. MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart. Eur Heart J. 2016;37(6):572–6.
Khadrawy O, Gebremedhn S, Salilew-Wondim D, Taqi MO, Neuhoff C, Tholen E, et al. Endogenous and Exogenous Modulation of Nrf2 mediated oxidative stress response in bovine granulosa cells: potential implication for ovarian function. Int J Mol Sci. 2019;20:7.
Zhang F, Cheng N, Du J, Zhang H, Zhang C. MicroRNA-200b-3p promotes endothelial cell apoptosis by targeting HDAC4 in atherosclerosis. BMC Cardiovasc Disord. 2021;21(1):172.
Yu M, Liu Y, Zhang B, Shi Y, Cui L, Zhao X. Inhibiting microRNA-144 abates oxidative stress and reduces apoptosis in hearts of streptozotocin-induced diabetic mice. Cardiovasc Pathol. 2015;24(6):375–81.
Mogilevsky M, Shimshon O, Kumar S, Mogilevsky A, Keshet E, Yavin E, et al. Modulation of MKNK2 alternative splicing by splice-switching oligonucleotides as a novel approach for glioblastoma treatment. Nucleic Acids Res. 2018;46(21):11396–404.
Maimon A, Mogilevsky M, Shilo A, Golan-Gerstl R, Obiedat A, Ben-Hur V, et al. Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation. Cell Rep. 2014;7(2):501–13.
Li Y, Duan JZ, He Q, Wang CQ. miR-155 modulates high glucose-induced cardiac fibrosis via the Nrf2/HO-1 signaling pathway. Mol Med Rep. 2020;22(5):4003–16.
Baseler WA, Thapa D, Jagannathan R, Dabkowski ER, Croston TL, Hollander JM. miR-141 as a regulator of the mitochondrial phosphate carrier (Slc25a3) in the type 1 diabetic heart. Am J Physiol Cell Physiol. 2012;303(12):C1244–51.
Li H, Dai B, Fan J, Chen C, Nie X, Yin Z, et al. The Different Roles of miRNA-92a-2-5p and let-7b-5p in Mitochondrial Translation in db/db Mice. Mol Ther Nucleic Acids. 2019;17:424–35.
Zhan H, Huang F, Niu Q, Jiao M, Han X, Zhang K, et al. Downregulation of miR-128 Ameliorates Ang II-Induced Cardiac Remodeling via SIRT1/PIK3R1 Multiple Targets. Oxid Med Cell Longev. 2021;2021:8889195.
Ruiz-Velasco A, Zi M, Hille SS, Azam T, Kaur N, Jiang J, et al. Targeting mir128–3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure. Elife. 2020;9:18.
Zhao D, Shun E, Ling F, Liu Q, Warsi A, Wang B, et al. Plk2 Regulated by miR-128 Induces Ischemia-Reperfusion Injury in Cardiac Cells. Mol Ther Nucleic Acids. 2020;19:458–67.
Zhang X, Zuo X, Yang B, Li Z, Xue Y, Zhou Y, et al. MicroRNA directly enhances mitochondrial translation during muscle differentiation. Cell. 2014;158(3):607–19.
Santovito D, Weber C. Non-canonical features of microRNAs: paradigms emerging from cardiovascular disease. Nat Rev Cardiol. 2022.
Huang F, Gonçalves C, Bartish M, Rémy-Sarrazin J, Issa ME, Cordeiro B, et al. Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses. J Clin Invest. 2021;131(8): e140752.
Ke XY, Chen Y, Tham VY, Lin RY, Dakle P, Nacro K, et al. MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma. Oncogene. 2021;40(10):1851–67.
Xie J, Shen K, Jones AT, Yang J, Tee AR, Shen MH, et al. Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis. Cell Mol Life Sci. 2021;78(1):249–70.
Xu W, Kannan S, Verma CS, Nacro K. Update on the Development of MNK Inhibitors as Therapeutic Agents. J Med Chem. 2022;65(2):983–1007.
Sandeman LY, Kang WX, Wang X, Jensen KB, Wong D, Bo T, et al. Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity. Mol Metab. 2020;42: 101054.
Moore CE, Pickford J, Cagampang FR, Stead RL, Tian S, Zhao X, et al. MNK1 and MNK2 mediate adverse effects of high-fat feeding in distinct ways. Sci Rep. 2016;6:23476.
Liu H, Gong Z, Li K, Zhang Q, Xu Z, Xu Y. SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma. J Exp Clin Cancer Res. 2021;40(1):75.
Akoumianakis I, Polkinghorne M, Antoniades C. Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications. Nat Rev Cardiol. 2022. https://doi.org/10.1038/s41569-022-00718-5.
Faria A, Persaud SJ. Cardiac oxidative stress in diabetes: Mechanisms and therapeutic potential. Pharmacol Ther. 2017;172:50–62.