Research Paper Volume 14, Issue 14 pp 5925—5945

miR-21 upregulation exacerbates pressure overload-induced cardiac hypertrophy in aged hearts

Wei-Ting Chang1,2,3, , Jhih-Yuan Shih2,4, , Yu-Wen Lin1, , Tzu-Ling Huang1, , Zhih-Cherng Chen1, , Chi-Long Chen5,6, , Jan-Show Chu5,6, , Ping Yen Liu1,7, ,

  • 1 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
  • 2 Department of Internal Medicine, Division of Cardiology, Chi-Mei Medical Center, Tainan, Taiwan
  • 3 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
  • 4 Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
  • 5 Department of Pathology, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
  • 6 Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan
  • 7 Department of Internal Medicine, Division of Cardiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Received: February 14, 2022       Accepted: July 21, 2022       Published: July 28, 2022
How to Cite

Copyright: © 2022 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Young and aging hearts undergo different remodeling post pressure overload, but the regulator that determines responses to pressure overload at different ages remains unknown. With an angiotensin II (Ang II)-induced hypertensive model, miR-21 knockout mice (miR-21−/−) were observed regarding the effects of miR-21 on hypertension-induced cardiac remodeling in young (12 week-old) and old (50 week-old) mice. Although the aged heart represented a more significant hypertrophy and was associated with a higher expression of miR-21, Ang II-induced cardiac hypertrophy was attenuated in miR-21−/− mice. Upon results of cardiac-specific arrays in miR-21-overexpressing cardiomyocytes, we found a significant downregulation of S100a8. In both in vitro and in vivo models, miR-21/S100a8/NF-κB/NFAT pathway was observed to be associated with pressure overload-induced hypertrophic remodeling in aged hearts. To further investigate whether circulating miR-21 could be a biomarker reflecting the aged associated cardiac remodeling, we prospectively collected clinical and echocardiographic information of patients at young (<65 y/o) and old ages (≥65 y/o) with and without hypertension. Among 108 patients, aged subjects presented with a significantly higher expression of circulating miR-21, which was positively correlated with left ventricular wall thickness. Collectively, miR-21 was associated with a prominently hypertrophic response in aged hearts under pressure overload. Further studies should focus on therapeutic potentials of miR-21.


Ang II: angiotensin II; miRNAs: microRNAs; miR-21−/−: miR-21 knockout; qPCR: quantitative PCR; SPSS: Statistical Package for the Social Sciences; IVSd: intraventricular septal thickness at diastole; LVIDd: left ventricular internal diameter in diastole; EF: ejection fraction; FS: fractional shortening; LVEF: left ventricular ejection fraction; LVMI: left ventricular mass index; EDV: end-diastolic volume; ESV: end-systolic volume; LAVi: left atrial volume index; e: peak early filling velocity; a: peak atrial velocity; e’: early diastolic annular velocity; a’: atrial annular velocity; e/e’: left ventricular end-diastolic pressure; TRF2: Telomeric repeat-binding factor 2; TERT: Telomerase reverse transcriptase; BNP: B-type Natriuretic Peptide; ANP: Atrial natriuretic peptide; MyH7: Myosin Heavy Chain 7; CTnl: Cardiac-specific Troponin I; LDH: Lactic dehydrogenase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NFAT: Nuclear factor of activated T-cells; Nr3C2: Nuclear Receptor Subfamily 3 Group C Member 2; NKX2.5: NK2 Homeobox 5; SDS: sodium dodecyl sulfate-polyacrylamide; PVDF: polyvinylidene fluoride.