miR-424/322 attenuates cardiac remodeling by modulating the nuclear factor-activated T-cell 3/furin pathway

Hsiao-Ya Tsai; Jen-Chun Wang; Yu-Juei Hsu; Chih-Yuan Lin; Po-Hsun Huang; Min-Chien Tsai; Chin-Wang Hsu; Shang-Feng Yang; Shih-Hung Tsai

doi:10.1016/j.bj.2024.100818

miR-424/322 attenuates cardiac remodeling by modulating the nuclear factor-activated T-cell 3/furin pathway

Biomed J. 2024 Nov 23:100818. doi: 10.1016/j.bj.2024.100818. Online ahead of print.

Authors

Hsiao-Ya Tsai¹, Jen-Chun Wang², Yu-Juei Hsu³, Chih-Yuan Lin⁴, Po-Hsun Huang⁵, Min-Chien Tsai⁶, Chin-Wang Hsu⁷, Shang-Feng Yang⁸, Shih-Hung Tsai⁹

Affiliations

¹ Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
² Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁴ Department of Surgery, Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁵ Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶ Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan.
⁷ Department of Emergency Medicine, School of Medicine, College of Medicine; Taipei Medical University, Taipei, Taiwan; Department of Emergency and Critical Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
⁸ Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan; Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan. Electronic address: samyang1223@gmail.com.
⁹ Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan; Taichung Armed Forces General Hospital, Taichung, Taiwan. Electronic address: tsaishihung@ndmctsgh.edu.tw.

PMID: 39586376
DOI: 10.1016/j.bj.2024.100818

Abstract

Background: Cardiac remodeling is implicated in numerous physiologic and pathologic conditions, including scar formation, heart failure, and cardiac arrhythmias. Nuclear factor-activated T-cell cytoplasmic (NFATc) is a crucial transcription factor that regulates cardiac remodeling. MicroRNA (miR)-424/322 has pathophysiological roles in the cardiovascular and respiratory systems by modulating hypoxia and inflammatory pathways. The role of miR-424/322 in regulating cardiac remodeling is under investigation. We identified several cardiac hypertrophy and fibrosis-related molecules as putative targets of miR-424/322. We propose that miR-424/322 could have crucial roles in cardiac remodeling by modulating several key molecules for cardiac fibrosis and hypertrophy.

Methods: Human cardiac fibroblasts (HCFs) and a myogenic cell line H9c2 cells were used for in vitro experiments. A murine model of angiotensin II (AngII)-induced cardiac remodeling was used to assess the roles of miR-322 on cardiac hypertrophy and fibrosis in vivo. Immunoblotting, immunofluorescence, real-time polymerase chain reaction and cell proliferation, Sirius Red, and dual-luciferase reporter assays were used to decipher the molecular mechanism.

Results: We found that miR-322 knockout mice were susceptible to AngII-induced cardiac fibrosis and hypertrophy in vivo. Administration of miR-424/322 inhibitors aggravated AngII-induced overexpression of NFATc3, furin, natriuretic peptides and collagen 1A1 in H9c2 cells and HCFs. miR-424/322 mimics reversed the AngII-induced fibrosis, hypertrophy, and proliferation by targeting NFATc3 and furin in vitro. miR-424/322 could be transactivated by NFATc3. Exogenous miR-322 ameliorated AngII-induced hypertrophy and cardiac fibrosis in vivo.

Conclusions: The NFATc3/miR-424/322/furin axis is crucial for developing cardiac remodeling, and exogenous miR-322 mimics could have therapeutic potential in cardiac remodeling.

Keywords: Nuclear factor-activated T cell; angiotensin II; cardiac remodeling; furin; hypertrophy; miR-424/322.