Curcumin attenuates pressure overload-induced cardiac fibrosis in mice via modulating the miR-29b/HDAC4 axis

Abstract

Objective: To investigate the antifibrotic effects of curcumin in a transverse aortic constriction (TAC) mouse model and elucidate its molecular mechanisms.

Methods: Male C57BL/6 mice underwent TAC and received vehicle, low-dose curcumin (50 mg/kg), high-dose curcumin (200 mg/kg), high-dose curcumin plus a scrambled control antagomir, or high-dose curcumin plus anti-miR-29b treatments. Cardiac function was assessed by echocardiography. Fibrosis was evaluated by histology, collagen volume fraction, and hydroxyproline content. Expression of miR-29b, HDAC4, and fibrosis-related markers (Collai, Col3a1, TGF-β1) was measured by quantitative RT-PCR and Western blotting assays. Myocardial procollagen type I carboxyterminal propeptide was determined by ELISA, and HDAC4-specific enzymatic activity was assayed using a fluorogenic kit.

Results: Curcumin improved cardiac function, reduced fibrosis, restored miR-29b expression, and suppressed HDAC4 expression and activity in a dose-dependent manner. Furthermore, curcumin decreased myocardial procollagen type I carboxy-terminal propeptide levels, confirming reduced collagen synthesis. Anti-miR-29b administration partially abrogated the antifibrotic and cardioprotective effects of curcumin.

Conclusions: Curcumin attenuates pressure overload-induced cardiac fibrosis and dysfunction in a TAC mouse model via modulation of the miR-29b/HDAC4 axis and suppression of collagen synthesis.

Keywords

Curcumin / Cardiac fibrosis / MiR-29b / HDAC4 / Heart failure / Pressure overload

Conflict of interest statement

The authors declare that there is no conflict of interest.

Funding

This study was supported by China International Medical Foundation (Z-2019-42-1908-4) and Natural Science Basic Research Program of Shaanxi Province (2019JM-440).

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon request.

Authors’ contributions

YX developed and planned the study, designed the methodology, curated the data, and wrote the original draft. JL contributed to the conceptualization, and reviewed and edited the manuscript. XXL, BTL, and YL participated in the methodology design. All authors have read and approved the final version of the manuscript.

Publisher’s note

The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

[1] Frangogiannis NG. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Circ Res 2021; 128(6): 830-852. doi: 10.1016/j.mam.2018.07.001.

[2] Cheng MH, Kuo HF, Chang CY, Chang JC, Liu IF, Hsieh CC, et al. Curcumin regulates pulmonary extracellular matrix remodeling and mitochondrial function to attenuate pulmonary fibrosis by regulating the miR-29a-3p/DNMT3A axis. Biomed Pharmacother 2024; 174. doi: 10.1016/j.biopha.2024.116572.

[3] Czubryt MP, Hale TM. Cardiac fibrosis: Pathobiology and therapeutic targets. Cell Signal 2021; 85. doi: 10.1016/j.cellsig.2021.110066.

[4] Li F, Li SS, Chen H, Zhao JZ, Hao J, Liu JM, et al. miR-320 accelerates chronic heart failure with cardiac fibrosis through activation of the IL6/STAT3 axis. Aging (Albany NY) 2021; 13(18): 22516-22527. doi: 10.18632/aging.203562.

[5] Bernardo BC, Ooi JYY, Lin RCY, McMullen JR. miRNA therapeutics: A new class of drugs with potential therapeutic applications in the heart. Cardiovasc Res 2020; 116(4): 754-772. doi: 10.18632/aging.203562.

[6] He Y, Dai MS, Tao LY, Gu X, Wang H, Liu P. Pericarpium Trichosanthis inhibits TGFβ1-Smad3 pathway-induced cardiac fibrosis in heart failure rats via upregulation of microRNA-29b. J Gene Med 2025; 27(1). doi: 10.1002/jgm.70003.

[7] Jiang G, Wang K, Zhang Y. Targeting histone deacetylases for heart diseases. Bioorg Chem 2023; 138. doi: 10.1016/j.bioorg.2023.106601.

[8] Liu J, You Y, Sun Z, Zhang L, Li X, Dai Z, et al. WTAP-mediated m6A RNA methylation regulates the differentiation of bone marrow mesenchymal stem cells via the miR-29b-3p/HDAC4 axis. Stem Cells Transi Med 2023; 12(5): 307-321. doi: 10.1093/stcltm/szad020.

[9] Heidari H, Bagherniya M, Majeed M. Curcumin-piperine cosupplementation and human health: A comprehensive review of preclinical and clinical studies. Phytother Res 2023; 37(4): 1462-1487. doi: 10.1002/ptr.7737.

[10] Widowati W, Laksmitawati DR, Pratami DK, Rahmat D, Ravi Kiran S, Achyutha Devi J, et al. Protective effects of turmeric extract, curcumin, demethoxycurcumin, bis-demethoxycurcumin, and ar-turmerone from Curcuma longa L. rhizomes on acetaminophen-induced hepatotoxicity in HepG2 cells. Asian Pac J Trop Biomed 2025; 15(6): 251-262.

[11] Meng Z, Yu XH, Chen J, Li L, Li S. Curcumin attenuates cardiac fibrosis in spontaneously hypertensive rats through PPAR-γactivation. Acta Pharmacol Sin 2014; 35(10): 1247-1256. doi: 10.1038/aps.2014.63.

[12] Yu W, Wu J, Cai F, Xiang J, Zha W, Fan D, et al. Curcumin alleviates diabetic cardiomyopathy in experimental diabetic rats. PLoS One 2012; 7(12). doi: 10.1371/journal.pone.0052013.

[13] Li T, Jin J, Pu F, Bai Y, Chen Y, Li Y, et al. Cardioprotective effects of curcumin against myocardial I/R injury: A systematic review and metaanalysis of preclinical and clinical studies. Front Pharmacol 2023; 14. doi: 10.3389/fphar.2023.1111459.

[14] Rockman HA, Ross RS, Harris AN, Knowlton KU, Steinhelper ME, Field LJ, et al. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc Natl Acad Sci U S A 1991; 88(18): 8277-8281.

[15] Gorabi AM, Hajighasemi S, Kiaie N, Rosano GMC, Sathyapalan T, Al-Rasadi K, et al. Anti-fibrotic effects of curcumin and some of its analogues in the heart. Heart Fail Rev 2020; 25(5): 731-743. doi: 10.1007/s10741-019-09854-6.

[16] Sadoughi F, Hallajzadeh J, Mirsafaei L, Asemi Z, Zahedi M, Mansournia MA, et al. Cardiac fibrosis and curcumin: A novel perspective on this natural medicine. Mol Biol Rep 2021; 48(11): 7597-7608. doi: 10.1007/s11033-021-06768-1.

[17] Yue H, Zhao X, Liang W, Qin X, Bian L, He K, et al. Curcumin, novel application in reversing myocardial fibrosis in the treatment for atrial fibrillation from the perspective of transcriptomics in rat model. Biomed Pharmacother 2022; 146. doi: 10.1016/j.biopha.2021.112522.

[18] Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: The fibroblast awakens. Circ Res 2016; 118(6): 1021-1040. doi: 10.1161/CIRCRESAHA.115.306565.

[19] Li C, Wang N, Rao P, Wang L, Lu D, Sun L. Role of the microRNA-29 family in myocardial fibrosis. J Physiol Biochem 2021; 77(3): 365-376. doi: 10.1007/s13105-021-00814-z.

[20] Lu J, Qian S, Sun Z. Targeting histone deacetylase in cardiac diseases. Front Physiol 2024; 15. doi: 10.3389/fphys.2024.1405569.

[21] Weng L, Ye J, Yang F, Jia S, Leng M, Jia B, et al. TGF-β1/SMAD 3 regulates programmed cell death 5 that suppresses cardiac fibrosis postmyocardial infarction by inhibiting HDAC3. Circ Res 2023; 133(3): 237-251. doi: 10.1161/CIRCRESAHA.123.322596.

[22] Theodoropoulou MA, Mantzourani C, Kokotos G. Histone deacetylase inhibitors as a novel therapeutic option against fibrotic and inflammatory diseases. Biomolecules 2024; 14(12). doi: 10.3390/biom14121605.