Yaşa Bağlı Kalp Fonksiyon Değişiklikleri ve miRNA’lar

Amaç: Kalp fonksiyonundaki değişimler ile gen ifadelerindeki değişimler arasında yakın ilişkiler olduğu ve özellikle gen ifadesi sonrası modifikasyonların bu değişimlerde başta rol aldığı bilinmektedir. Ancak kalpteki mikroRNA’ların (miRNA) yapısal değişimlerle ilişkisi henüz tam olarak aydınlatılamamıştır. Bu çalışmada yaşa bağlı seyreden yapısal değişimlerin miRNA gen ifade düzeyleriyle olan ilişkisinin araştırılması hedeflenmiştir. Gereç ve Yöntem: Bu çalışmada Wistar türü erkek sıçanlar kullanılmıştır. Sıçanlar 3 aylık genç-yetişkin ve 12 aylık ileri-yaş-yetişkin olarak gruplandırılmıştır. Kalp doku kesitleri hematoksilin ve eozin ve masson trikrom boyama protokolü uygulanarak ışık mikroskobunda incelenmiştir. Kalp dokusu homojenatından miRNA izolasyonu hazır kitler kullanılarak yapılmış, ifade düzeyleri ise qt-PCR ile ölçülmüştür. Bulgular: Histolojik bulgular kalbin sol ventrikül kısmında kalp kası liflerinde hipertrofi ve özellikle endomisyal alanda artan sayıda fibroblastlar ve bağ dokusu elemanlarının olduğunu göstermiştir. Öte yandan yaşlanmayla birlikte endomisyum kılıfı lif yoğunluğunda belirgin bir fibroz yapılanması gözlenmiştir. Biyokimyasal sonuçlar miRNA-1 miRNA-133a ve miRNA-133b gen ifade düzeylerinin azaldığını göstermektedir. Sonuç: Çalışma sonuçları, sıçan kalp dokusunda yaşa paralel olarak miRNA gen ifade düzeylerindeki azalmanın yapısal ve fonksiyonel değişimlere aracılık ettiğini düşündürmektedir. Bu sonuçlar, yaşlanmanın etiyolojisini anlamak için miRNA’larla ilgili yeni tanı-tedavi hedeflerinin gerçekleştirilmesi açısından önemli olduğunu işaret etmektedir.

Age-related Alterations in Cardiac Function and miRNA’s

Objectives: Since changes in cardiac function are closely related to alterations in cardiac gene-expression, post-gene expression modifications exert an important role in these changes. However, the relationship between cardiac miRNAs and structural changes has not been fully elucidated yet. In this study, we aimed to investigate the relationship between structural changes and miRNA gene expression levels in senescent heart. Materials and Methods: Wistar type male rats were used in this study. Rats were grouped as 3-month-old young-adults and 12-month-old adults. Cardiac tissue sections were examined under a light microscope using hematoxylin and eosin and masson trichrome staining protocol. Isolation of miRNA from cardiac tissue homogenate was performed using commercial kits and expression levels were determined by qt-PCR. Results: Histological findings showed that there was hypertrophy in muscle fibers, and an increasing number of fibroblasts and connective tissue elements, especially in the endomysial area in left ventricular tissue. On the other hand, a marked fibrosis was observed in the endomysium fiber density during aging. Biochemical results showed that miRNA-1 miRNA-133a and miRNA-133b gene expression levels were significantly decreased. Conclusion: It suggests that the decrease in miRNA gene expression levels with aging mediates structural and functional changes. These results are important in terms of achieving new treatment-diagnostic goals related to miRNAs to understand the etiology of aging.

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1. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003;107:346-354.
2. Ferrucci L. The Baltimore Longitudinal Study of Aging (BLSA): a 50-yearlong journey and plans for the future. J Gerontol A Biol Sci Med Sci. 2008;63:1416-1419.
3. Ferrucci L, Giallauria F, Guralnik JM. Epidemiology of aging. Radiol Clin North Am. 2008;46:643-652.
4. Fink RI, Kolterman OG, Griffin J, Olefsky JM. Mechanisms of insulin resistance in aging. J Clin Invest. 1983;71:1523-1535.
5. Escrivá F, Gavete ML, Fermín Y, et al. Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity. J Endocrinol. 2007;194:131-141.
6. Evans JL, Goldfine ID. Aging and insulin resistance: just say iNOS. Diabetes. 2013;62:346-348.
7. Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging. Circulation. 2003;107:490-497.
8. Antelmi I, de Paula RS, Shinzato AR, et al. Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease. Am J Cardiol. 2004;93:381-385.
9. Li H, Hastings MH, Rhee J, et al. Targeting Age-Related Pathways in Heart Failure. Circ Res. 2020;126:533-551.
10. Olgar Y, Degirmenci S, Durak A, et al. Aging related functional and structural changes in the heart and aorta: MitoTEMPO improves aged-cardiovascular performance. Exp Gerontol. 2018;110:172-181.
11. Olgar Y, Billur D, Tuncay E, et al. MitoTEMPO provides an antiarrhythmic effect in aged-rats through attenuation of mitochondrial reactive oxygen species. Exp Gerontol. 2020;136:110961.
12. Volkova M, Garg R, Dick S, et al. Aging-associated changes in cardiac gene expression. Cardiovasc Res. 2005;66:194-204.
13. Lieber MR, Karanjawala ZE. Ageing, repetitive genomes and DNA damage. Nat Rev Mol Cell Biol. 2004;5:69-75.
14. Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000;14:1021-1026.
15. Latronico MV, Condorelli G. MicroRNAs and cardiac pathology. Nat Rev Cardiol. 2009;6:419-429.
16. Hennessy E, O’Driscoll L. Molecular medicine of microRNAs: structure, function and implications for diabetes. Expert Rev Mol Med. 2008;10:e24.
17. Horn MA, Trafford AW. Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling. J Mol Cell Cardiol. 2016;93:175-185.
18. Sheydina A, Riordon DR, Boheler KR. Molecular mechanisms of cardiomyocyte aging. Clin Sci (Lond). 2011;121:315-329.
19. Chen LH, Chiou GY, Chen YW, et al. MicroRNA and aging: a novel modulator in regulating the aging network. Ageing Res Rev. 2010;9:59-66.
20. Sayed AS, Xia K, Yang TL, et al. Circulating microRNAs: a potential role in diagnosis and prognosis of acute myocardial infarction. Dis Markers. 2013;35:561-566.
21. Zhang J, Ney PA. Autophagy-dependent and -independent mechanisms of mitochondrial clearance during reticulocyte maturation. Autophagy. 2009;5:1064-1065.
22. Qian L, Pan S, Shi L, et al. Downregulation of microRNA-218 is cardioprotective against cardiac fibrosis and cardiac function impairment in myocardial infarction by binding to MITF. Aging (Albany NY). 2019;11:5368- 5388.
23. de Lucia C, Komici K, Borghetti G, et al. microRNA in Cardiovascular Aging and Age-Related Cardiovascular Diseases. Front Med (Lausanne). 2017;4:74.
24. Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heart disease. Physiol Genomics. 2007;31:367-373.
25. Carè A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med. 2007;13:613-618.
26. Tatsuguchi M, Seok HY, Callis TE, et al. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol. 2007;42:1137-1141.
27. van Rooij E, Sutherland LB, Thatcher JE, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A. 2008;105:13027-13032.
28. Kandilci HB, Tuncay E, Zeydanli EN, ve ark. Age-related regulation of excitation-contraction coupling in rat heart. J Physiol Biochem. 2011;67:317-330.
29. Ma F, Liu X, Li D, et al. MicroRNA-466l upregulates IL-10 expression in TLRtriggered macrophages by antagonizing RNA-binding protein tristetraprolinmediated IL-10 mRNA degradation. J Immunol. 2010;184:6053-6059.
30. Yildirim SS, Akman D, Catalucci D, et al. Relationship between downregulation of miRNAs and increase of oxidative stress in the development of diabetic cardiac dysfunction: junctin as a target protein of miR-1. Cell Biochem Biophys. 2013;67:1397-1408.
31. Akdas S, Turan B, Durak A, et al. The Relationship Between Metabolic Syndrome Development and Tissue Trace Elements Status and Inflammatory Markers. Biol Trace Elem Res. 2020;198:16-24.
32. Durak A, Olgar Y, Degirmenci S, et al. A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats. Cardiovasc Diabetol. 2018;17:144.
33. Durak A, Olgar Y, Tuncay E, et al. Onset of decreased heart work is correlated with increased heart rate and shortened QT interval in high-carbohydrate fed overweight rats. Can J Physiol Pharmacol. 2017;95:1335-1342.
34. Okatan EN, Durak AT, Turan B. Electrophysiological basis of metabolicsyndrome- induced cardiac dysfunction. Can J Physiol Pharmacol. 2016;94:1064-1073.
35. Okatan EN, Tuncay E, Hafez G, et al. Profiling of cardiac β-adrenoceptor subtypes in the cardiac left ventricle of rats with metabolic syndrome: Comparison with streptozotocin-induced diabetic rats. Can J Physiol Pharmacol. 2015;93:517-525.
36. Courboulin A, Paulin R, Giguère NJ, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208:535-548.
37. Jeon YJ, Kim OJ, Kim SY, et al. Association of the miR-146a, miR-149, miR- 196a2, and miR-499 polymorphisms with ischemic stroke and silent brain infarction risk. Arterioscler Thromb Vasc Biol. 2013;33:420-430.
38. Goren Y, Meiri E, Hogan C, et al. Relation of reduced expression of MiR- 150 in platelets to atrial fibrillation in patients with chronic systolic heart failure. Am J Cardiol. 2014;113:976-981.
39. Wronska A, Kurkowska-Jastrzebska I, Santulli G. Application of microRNAs in diagnosis and treatment of cardiovascular disease. Acta Physiol (Oxf). 2015;213:60-83.
40. Olgar Y, Degirmenci S, Durak A, et al. Aging related functional and structural changes in the heart and aorta: MitoTEMPO improves aged-cardiovascular performance. Exp Gerontol. 2018;110:172-181.
41. O’Reilly S. MicroRNAs in fibrosis: opportunities and challenges. Arthritis Res Ther. 2016;18:11.
42. Li N, Zhou H, Tang Q. miR-133: A Suppressor of Cardiac Remodeling? Front Pharmacol. 2018;9:903.
43. Rao PK, Toyama Y, Chiang HR, et al. Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure. Circ Res. 2009;105:585-594.