Polidatinin İzoproterenol-indüklenen Patolojik Kardiyak Hipertrofiyi miR-214/FOXO3/NFAT Ekseni Üzerinden Azaltıcı Etkisinin İncelenmesi

Atıf

Paylaş

Özgün Araştırma

CİLT: 14 SAYI: 2

P: 134 - 143

Haziran 2026

Polidatinin İzoproterenol-indüklenen Patolojik Kardiyak Hipertrofiyi miR-214/FOXO3/NFAT Ekseni Üzerinden Azaltıcı Etkisinin İncelenmesi

Namik Kemal Med J 2026;14(2):134-143

DOI: 10.4274/nkmj.galenos.2026.07088

Bilge Eren YAMASAN

Bilgi mevcut değil.

Bilgi mevcut değil

Alındığı Tarih: 18.11.2025

Kabul Tarihi: 20.01.2026

Online Tarih: 16.06.2026

Yayın Tarihi: 16.06.2026

Atıf

Paylaş

ÖZ

Amaç

Patolojik kardiyak hipertrofi, kalp yetersizliğinin erken bir habercisidir ve miyokardın yapısını, işlevini ve moleküler sinyal yollarını değiştirir. miRNA’lar, özellikle miR-214, yeniden şekillenme ve hipertrofi ile ilişkili temel yolları düzenler. Polidatinin kardiyoprotektif etkileri daha önce bildirilmiş olsa da, bu etkilerin miRNA-bağımlı mekanizmalarla gerçekleşip gerçekleşmediği belirsizdir. Bu çalışma, polidatinin etkilerinde miR-214/Forkhead box O3 (FOXO3)/nükleer faktör aktivasyon T-hücreleri (NFAT) ekseninin olası rolünü araştırmayı amaçlamaktadır.

Gereç ve Yöntem

Erkek Wistar sıçanları üç gruba ayrıldı: Kontrol, İzoproterenol (ISO); 5 mg/kg/gün, cilt altı) ve ISO + polidatin (100 mg/kg/gün, oral). Dört haftalık tedavi sonrası kalp ağırlığı, kalp ağırlığı/vücut ağırlığı oranı ve kalp ağırlığı/tibia uzunluğu oranı ölçülerek kardiyak hipertrofi değerlendirildi. Moleküler analizler için miR-1, miR-214 ve miR-133b düzeyleri ile FOXO3, NFAT, atriyal natriüretik peptit (ANP) ve beyin natriüretik peptidi (BNP) mRNA düzeyleri gerçek zamanlı polimeraz zincir reaksiyonu yöntemiyle ölçüldü.

Bulgular

Morfolojik parametreler, ISO grubunda kontrol grubuna kıyasla anlamlı düzeyde arttı (p<0,001) ve bu artışlar polidatin tedavisi ile belirgin şekilde baskılandı (p<0,05). İncelenen miRNA’lar arasında yalnızca miR-214 düzeyi ISO grubunda anlamlı olarak yükseldi (p=0,006), polidatin tedavisi ise bu artışı azalttı (p=0,030). ISO uygulaması FOXO3 ekspresyonunu baskıladı (p=0,027) ve NFAT ekspresyonunu arttırdı (p<0,001). Polidatin ise bu değişiklikleri tersine çevirdi. Fetal gen belirteçleri olan ANP (p=0,029) ve BNP (p=0,002) düzeyleri ISO grubunda anlamlı şekilde yükselirken, polidatin tedavisi sonrasında bu artışlar ortadan kalktı ve düzeyler kontrol grubundan farklı bulunmadı (kontrole göre p>0,05).

Sonuç

Polidatin, ISO kaynaklı patolojik kardiyak hipertrofiye karşı kardiyoprotektif etkiler göstermektedir. Bu etkiler yalnızca morfolojik düzelmelerle sınırlı değildir; aynı zamanda miR-214/FOXO3/NFAT ekseni üzerinden moleküler düzenlemeyi ve fetal gen programının baskılanmasını da içerir. Bulgular, polidatinin patolojik kardiyak yeniden şekillenmenin önlenmesinde potansiyel bir farmakolojik ajan olabileceğini göstermektedir.

Anahtar Kelimeler:

Polidatin, kardiyak hipertrofi, miR-214, Forkhead box O3 (FOXO3), nükleer faktör aktivasyon T-hücreleri (NFAT)

Kaynaklar

1

Martin TG, Juarros MA, Leinwand LA. Regression of cardiac hypertrophy in health and disease: mechanisms and therapeutic potential. Nat Rev Cardiol. 2023;20:347-63.

CrossRef PubMed Google Scholar

2

Oldfield CJ, Duhamel TA, Dhalla NS. Mechanisms for the transition from physiological to pathological cardiac hypertrophy. Can J Physiol Pharmacol. 2020;98:74-84.

CrossRef PubMed Google Scholar

3

Ritterhoff J, Tian R. Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges. Nat Rev Cardiol. 2023;20:812-29.

CrossRef PubMed Google Scholar

4

Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15:387-407.

CrossRef PubMed Google Scholar

5

Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol. 2016;97:245-62.

CrossRef PubMed Google Scholar

6

Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, et al. Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res. 2004;94:110-8.

7

Molkentin JD. Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res. 2004;63:467-75.

CrossRef PubMed Google Scholar

8

Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol. 2015;89:1401-38.

CrossRef PubMed Google Scholar

9

Chen J, Li J, Wang X, Zeng Z, Zhang H, Zou Z, et al. LincRNA RMRP Regulates phenylephrine-induced cardiomyocyte hypertrophy by means of targeting miR-1. J Cardiovasc Pharmacol. 2022;80:709-17.

10

Thum T, Condorelli G. Long noncoding RNAs and microRNAs in cardiovascular pathophysiology. Circ Res. 2015;116:751-62.

CrossRef PubMed Google Scholar

11

Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019; 234:5451-65.

CrossRef PubMed Google Scholar

12

Katz MG, Fargnoli AS, Kendle AP, Hajjar RJ, Bridges CR. The role of microRNAs in cardiac development and regenerative capacity. Am J Physiol Heart Circ Physiol. 2016;310:H528-41.

CrossRef PubMed Google Scholar

13

Dosil SG, Rodríguez-Galán A, Sánchez-Madrid F, Fernández-Messina L. MicroRNAs in T cell-immunotherapy. Int J Mol Sci. 2022;24:250.

14

Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci. 2016;17:1712.

CrossRef PubMed Google Scholar

15

Piccoli MT, Bär C, Thum T. Non-coding RNAs as modulators of the cardiac fibroblast phenotype. J Mol Cell Cardiol. 2016;92:75-81.

CrossRef PubMed Google Scholar

16

Kumarswamy R, Thum T. Non-coding RNAs in cardiac remodeling and heart failure. Circ Res. 2013;113:676-89.

CrossRef PubMed Google Scholar

17

Osmak G, Baulina N, Kiselev I, Favorova O. MiRNA-regulated pathways for hypertrophic cardiomyopathy: network-based approach to insight into pathogenesis. Genes (Basel). 2021;12:2016.

CrossRef PubMed Google Scholar

18

Scolari FL, Faganello LS, Garbin HI, Piva E Mattos B, Biolo A. A systematic review of microRNAs in patients with hypertrophic cardiomyopathy. Int J Cardiol. 2021;327:146-54.

CrossRef PubMed Google Scholar

19

Dong DL, Chen C, Huo R, Wang N, Li Z, Tu YJ, et al. Reciprocal repression between microRNA-133 and calcineurin regulates cardiac hypertrophy: a novel mechanism for progressive cardiac hypertrophy. Hypertension. 2010;55:946-52.

20

Shirazi-Tehrani E, Firouzabadi N, Tamaddon G, Bahramali E, Vafadar A. Carvedilol alters circulating MiR-1 and MiR-214 in heart failure. Pharmgenomics Pers Med. 2020; 13:375-83.

CrossRef PubMed Google Scholar

21

Amin MMJ, Trevelyan CJ, Turner NA. MicroRNA-214 in health and disease. Cells. 2021;10:3274.

CrossRef PubMed Google Scholar

22

Zhou SS, Jin JP, Wang JQ, Zhang ZG, Freedman JH, Zheng Y, et al. miRNAS in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges. Acta Pharmacol Sin. 2018;39:1073-84.

23

Zhang Y, Sun M, Wang D, Hu Y, Wang R, Diao H, et al. FTZ protects against cardiac hypertrophy and oxidative injury via microRNA-214 / SIRT3 signaling pathway. Biomed Pharmacother. 2022;148:112696.

24

Duan Q, Yang L, Gong W, Chaugai S, Wang F, Chen C, et al. MicroRNA-214 is upregulated in heart failure patients and suppresses XBP1-mediated endothelial cells angiogenesis. J Cell Physiol. 2015;230:1964-73.

25

Yang T, Gu H, Chen X, Fu S, Wang C, Xu H, et al. Cardiac hypertrophy and dysfunction induced by overexpression of miR-214 in vivo. J Surg Res. 2014;192:317-25.

26

S Silva J, da Costa Martins PA. Non-Coding RNAs in the therapeutic landscape of pathological cardiac hypertrophy. Cells. 2022;11:1805.

27

Ding YQ, Zhang YH, Lu J, Li B, Yu WJ, Yue ZB, et al. MicroRNA-214 contributes to Ang II-induced cardiac hypertrophy by targeting SIRT3 to provoke mitochondrial malfunction. Acta Pharmacol Sin. 2021;42:1422-36.

28

Zhang F, Geng L, Zhang J, Han S, Guo M, Xu Y, et al. miR-486-5p diagnosed atrial fibrillation, predicted the risk of left atrial fibrosis, and regulated angiotensin II-induced cardiac fibrosis via modulating PI3K/Akt signaling through targeting FOXO1. Mol Cell Biochem. 2025;480:1077-87.

29

Xin Z, Ma Z, Jiang S, Wang D, Fan C, Di S, et al. FOXOs in the impaired heart: new therapeutic targets for cardiac diseases. Biochim Biophys Acta Mol Basis Dis. 2017;1863:486-98.

30

Hong JH, Zhang HG. Transcription factors involved in the development and prognosis of cardiac remodeling. Front Pharmacol. 2022;13:828549.

CrossRef PubMed Google Scholar

31

Xie J, Zheng C, Shen M, Lu W, Li M, He M, et al. Pregnancy-induced physiological hypertrophic preconditioning attenuates pathological myocardial hypertrophy by activation of FoxO3a. Cell Mol Life Sci. 2023;80:267.

32

Ni YG, Berenji K, Wang N, Oh M, Sachan N, Dey A, et al. Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation. 2006;114:1159-68.

33

Sengupta A, Molkentin JD, Paik JH, DePinho RA, Yutzey KE. FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress. J Biol Chem. 2011;286:7468-78.

CrossRef PubMed Google Scholar

34

Yang J, Liu Y, Fan X, Li Z, Cheng Y. A pathway and network review on beta-adrenoceptor signaling and beta blockers in cardiac remodeling. Heart Fail Rev. 2014;19:799-814.

35

Yu W, Chen C, Cheng J. The role and molecular mechanism of FoxO1 in mediating cardiac hypertrophy. ESC Heart Fail. 2020;7:3497-504.

36

Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79:727-47.

CrossRef PubMed Google Scholar

37

Du QH, Peng C, Zhang H. Polydatin: a review of pharmacology and pharmacokinetics. Pharm Biol. 2013;51:1347-54.

38

Karami A, Fakhri S, Kooshki L, Khan H. Polydatin: pharmacological mechanisms, therapeutic targets, biological activities, and health benefits. Molecules. 2022;27:6474.

CrossRef PubMed Google Scholar

39

Tan YY, Chen LX, Fang L, Zhang Q. Cardioprotective effects of polydatin against myocardial injury in diabetic rats via inhibition of NADPH oxidase and NF-κB activities. BMC Complement Med Ther. 2020;20:378.

40

Zhang Q, Tan Y, Zhang N, Yao F. Polydatin prevents angiotensin II-induced cardiac hypertrophy and myocardial superoxide generation. Exp Biol Med (Maywood). 2015;240:1352-61.

41

Mattera R, Benvenuto M, Giganti MG, Tresoldi I, Pluchinotta FR, Bergante S, et al. Effects of polyphenols on oxidative stress-mediated injury in cardiomyocytes. Nutrients. 2017;9:523.

42

Sun Z, Wang X, Pang X. Potential of polydatin against ischemia-reperfusion injury: new insights from pharmacological-pathological mechanism associations. Drug Des Devel Ther. 2025;19:1585-94.

CrossRef PubMed Google Scholar

43

Ding W, Dong M, Deng J, Yan D, Liu Y, Xu T, et al. Polydatin attenuates cardiac hypertrophy through modulation of cardiac Ca2+ handling and calcineurin-NFAT signaling pathway. Am J Physiol Heart Circ Physiol. 2014;307:H792-802.

44

Yamasan BE, Mercan T, Erkan O, Ozdemir S. Ellagic Acid Prevents Ca 2+ Dysregulation and improves functional abnormalities of ventricular myocytes via attenuation of oxidative stress in pathological cardiac hypertrophy. Cardiovasc Toxicol. 2021;21:630-41.

CrossRef PubMed Google Scholar

45

Nanda D, Pant P, Machha P, Sowpati DT, Kumarswamy R. Transcriptional changes during isoproterenol-induced cardiac fibrosis in mice. Front Mol Biosci. 2023;10:1263913.

CrossRef PubMed Google Scholar

46

Flori L, Lazzarini G, Spezzini J, Pirone A, Calderone V, Testai L, et al. The isoproterenol-induced myocardial fibrosis: a biochemical and histological investigation. Biomed Pharmacother. 2024;174:116534.

47

Liu Y, Liang Y, Zhang JF, Fu WM. MicroRNA-133 mediates cardiac diseases: mechanisms and clinical implications. Exp Cell Res. 2017;354:65-70.

48

Song Z, Gao R, Yan B. Potential roles of microRNA-1 and microRNA-133 in cardiovascular disease. Rev Cardiovasc Med. 2020;21:57-64.

49

Bontempo P, Capasso L, De Masi L, Nebbioso A, Rigano D. Therapeutic potential of natural compounds acting through epigenetic mechanisms in cardiovascular diseases: current findings and future directions. Nutrients. 2024;16:2399.

CrossRef PubMed Google Scholar