Skip to main content
SpringerLink
Log in

MircroRNA-145 Attenuates Cardiac Fibrosis Via Regulating Mitogen-Activated Protein Kinase Kinase Kinase 3

  • Original Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

This study aimed to explore the effect of microRNA (miR)-145 on cardiac fibrosis in heart failure mice and its target.

Methods

Experiments were carried out in mice receiving left coronary artery ligation, transverse aortic constriction (TAC), or angiotensin (Ang) II to trigger heart failure, and in cardiac fibroblasts (CFs) with Ang II-induced fibrosis.

Results

The miR-145 levels were decreased in the mice hearts of heart failure induced by myocardial infarction (MI), TAC or Ang II infusion, and in the Ang II-treated CFs. The impaired cardiac function was ameliorated by miR-145 agomiR in MI mice. The increased fibrosis and the levels of collagen I, collagen III, and transforming growth factor-beta (TGF-β) in MI mice were inhibited by miR-145 agomiR or miR-145 transgene (TG). The agomiR of miR-145 also attenuated the increases of collagen I, collagen III, and TGF-β in Ang II-treated CFs. Bioinformatics analysis and luciferase reporter assays indicated that mitogen-activated protein kinase kinase kinase 3 (MAP3K3) was a direct target gene of miR-145. MAP3K3 expression was suppressed by MiR-145 in CFs, while the MAP3K3 over-expression reversed the inhibiting effects of miR-145 agomiR on the Ang II-induced increases of collagen I, collagen III, and TGF-β in CFs.

Conclusion

These results indicated that miR-145 upregulation could improve cardiac dysfunction and cardiac fibrosis by inhibiting MAP3K3 in heart failure. Thus, upregulating miR-145 or blocking MAP3K3 can be used to treat heart failure and cardiac fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Park GS, An MK, Yoon JH, et al. Botulinum toxin type a suppresses pro-fibrotic effects via the JNK signaling pathway in hypertrophic scar fibroblasts. Arch Dermatol Res. 2019;311:807–14.

    Article  CAS  PubMed  Google Scholar 

  2. Fan D, Takawale A, Lee J, Kassiri Z. Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair. 2012;5:15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kwak HB. Aging, exercise, and extracellular matrix in the heart. J Exerc Rehabil. 2013;9:338–47.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Flevaris P, Vaughan D. The role of plasminogen activator inhibitor Type-1 in fibrosis. Semin Thromb Hemost. 2017;43:169–77.

    Article  CAS  PubMed  Google Scholar 

  5. Parichatikanond W, Luangmonkong T, Mangmool S, Kurose H. Therapeutic targets for the treatment of cardiac fibrosis and cancer: focusing on TGF-beta signaling. Front Cardiovasc Med. 2020;7:34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hanna A, Humeres C, Frangogiannis NG. The role of Smad signaling cascades in cardiac fibrosis. Cell Signal. 2021;77:109826.

    Article  CAS  PubMed  Google Scholar 

  7. To KKW, Fong W, Tong CWS, Wu M, Yan W, Cho WCS. Advances in the discovery of microRNA-based anticancer therapeutics: latest tools and developments. Expert Opin Drug Discov. 2020;15:63–83.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang B, Tian L, Xie J, Chen G, Wang F. Targeting miRNAs by natural products: a new way for cancer therapy. Biomed Pharmacother. 2020;130:110546.

    Article  CAS  PubMed  Google Scholar 

  9. Arcidiacono B, Chiefari E, Foryst-Ludwig A, et al. Obesity-related hypoxia via miR-128 decreases insulin-receptor expression in human and mouse adipose tissue promoting systemic insulin resistance. EBioMedicine. 2020;59:102912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cakmak HA, Demir M. MicroRNA and cardiovascular diseases. Balkan Med J. 2020;37:60–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kura B, Szeiffova Bacova B, Kalocayova B, Sykora M, Slezak J. Oxidative stress-responsive microRNAs in heart injury. Int J Mol Sci. 2020;21:358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang S, Zhang L, Song J, et al. Long noncoding RNA MALAT1 mediates cardiac fibrosis in experimental postinfarct myocardium mice model. J Cell Physiol. 2019;234:2997–3006.

    Article  CAS  PubMed  Google Scholar 

  13. Liu Y, Song JW, Lin JY, Miao R, Zhong JC. Roles of MicroRNA-122 in cardiovascular fibrosis and related diseases. Cardiovasc Toxicol. 2020;20:463–73.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yang X, Yu T, Zhang S. MicroRNA-489 suppresses isoproterenol-induced cardiac fibrosis by downregulating histone deacetylase 2. Exp Ther Med. 2020;19:2229–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang M, Cheng YJ, Sara JD, et al. Circulating MicroRNA-145 is associated with acute myocardial infarction and heart failure. Chin Med J. 2017;130:51–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu J, Huang Q, Li P, et al. MicroRNA-145 promotes the epithelial-mesenchymal transition in peritoneal dialysis-associated fibrosis by suppressing fibroblast growth factor 10. J Biol Chem. 2019;294:15052–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu Z, Tao B, Fan S, et al. Over-expression of microRNA-145 drives alterations in beta-adrenergic signaling and attenuates cardiac remodeling in heart failure post myocardial infarction. Aging (Albany NY). 2020;12:11603–22.

    Article  CAS  PubMed  Google Scholar 

  18. Xu Z, Sun J, Tong Q, et al. The role of ERK1/2 in the development of diabetic cardiomyopathy. Int J Mol Sci. 2016;17. https://doi.org/10.3390/ijms17122001

  19. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410:37–40.

    Article  CAS  PubMed  Google Scholar 

  20. Csak T, Bala S, Lippai D, et al. microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int. 2015;35:532–41.

    Article  CAS  PubMed  Google Scholar 

  21. Castillero E, Akashi H, Najjar M, et al. Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis. Am J Physiol Heart Circ Physiol. 2020;318:H378–H90.

    Article  CAS  PubMed  Google Scholar 

  22. Yang Z, Zhang X, Guo N, Li B, Zhao S. Substance P inhibits the collagen synthesis of rat myocardial fibroblasts induced by Ang II. Med Sci Monitor: Int Med J Exp Clin Res. 2016;22:4937–46.

    Article  CAS  Google Scholar 

  23. Yang X, Wang Y, Yan S, et al. Effect of testosterone on the proliferation and collagen synthesis of cardiac fibroblasts induced by angiotensin II in neonatal rat. Bioengineered. 2017;8:14–20.

    Article  CAS  PubMed  Google Scholar 

  24. Wolfien M, Klatt D, Salybekov AA, et al. Hematopoietic stem-cell senescence and myocardial repair - coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT phase 3. EBioMed. 2020;57:102862.

    Article  Google Scholar 

  25. Wojciechowska A, Braniewska A, Kozar-Kaminska K. MicroRNA in cardiovascular biology and disease. Adv Clin Exp Med. 2017;26:865–74.

    Article  PubMed  Google Scholar 

  26. Zhang J, Wei X, Zhang W, Wang F, Li Q. MiR-326 targets MDK to regulate the progression of cardiac hypertrophy through blocking JAK/STAT and MAPK signaling pathways. Eur J Pharmacol. 2020;872:172941.

    Article  CAS  PubMed  Google Scholar 

  27. Song JJ, Yang M, Liu Y, et al. MicroRNA-122 aggravates angiotensin II-mediated apoptosis and autophagy imbalance in rat aortic adventitial fibroblasts via the modulation of SIRT6-elabela-ACE2 signaling. Eur J Pharmacol. 2020;883:173374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dutka M, Bobinski R, Korbecki J. The relevance of microRNA in post-infarction left ventricular remodelling and heart failure. Heart Fail Rev. 2019;24:575–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vegter EL, van der Meer P, de Windt LJ, Pinto YM, Voors AA. MicroRNAs in heart failure: from biomarker to target for therapy. Eur J Heart Fail. 2016;18:457–68.

    Article  CAS  PubMed  Google Scholar 

  30. Sun D, Yang F. Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism. Biochem Biophys Res Commun. 2017;486:329–35.

    Article  CAS  PubMed  Google Scholar 

  31. Adapala RK, Kanugula AK, Paruchuri S, Chilian WM, Thodeti CK. TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation. Basic Res Cardiol. 2020;115:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Polegato BF, Minicucci MF, Azevedo PS, et al. Association between functional variables and heart failure after myocardial infarction in rats. Arq Bras Cardiol. 2016;106:105–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang K, Zhu ZF, Chi RF, et al. The NADPH oxidase inhibitor apocynin improves cardiac sympathetic nerve terminal innervation and function in heart failure. Exp Physiol. 2019;104:1638–49.

    Article  CAS  PubMed  Google Scholar 

  34. Gabisonia K, Prosdocimo G, Aquaro GD, et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature. 2019;569:418–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circ Res. 2016;118:1021–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cui S, Liu Z, Tao B, et al. miR-145 attenuates cardiac fibrosis through the AKT/GSK-3beta/beta-catenin signaling pathway by directly targeting SOX9 in fibroblasts. J Cell Biochem. 2021;122:209–21.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao L, Ni X, Zhao L, et al. MiroRNA-188 acts as tumor suppressor in non-small-cell lung Cancer by targeting MAP3K3. Mol Pharm. 2018;15:1682–9.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang L, Zhang Y, Wang S, et al. MiR-212-3p suppresses high-grade serous ovarian cancer progression by directly targeting MAP3K3. Am J Transl Res. 2020;12:875–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lv Y, Huang Y, Xu M, et al. The miR-193a-3p-MAP3k3 signaling Axis regulates substrate topography-induced Osteogenesis of bone marrow stem cells. Adv Sci (Weinh). 2020;7:1901412.

    Article  CAS  PubMed  Google Scholar 

  40. Yu C, Liu Y, Sun L, et al. Chronic obstructive sleep apnea promotes aortic remodeling in canines through miR-145/Smad3 signaling pathway. Oncotarget. 2017;8:37705–16.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sawant D, Klevenow E, Baeten JT, et al. Generation of transgenic mice that conditionally express microRNA miR-145. Genesis. 2020;58:e23385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Intensive Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Yun Liu & Weiwei Wang

  2. Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Jing Hu

  3. Pediatric Department, Shanghai General Hospital, No.650 Xinsongjiang Road, Shanghai, 201600, Songjiang District, China

    Qian Wang

Authors
  1. Yun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weiwei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Yun Liu performed the research. Jing Hu analyzed the data. Weiwei Wang wrote the paper. Qian Wang designed the research study and revised the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qian Wang.

Ethics declarations

Ethics Approval

The study was approved by the Ethical Committee on the Experimental Animal Care and Use Committee of Nanjing Medical University.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Fig. S1

The level of microRNA (miR)-145 after treating with miR-145 agomiR. (A) The level of miR-145 was increased in the hearts of mice after treating with miR-145 agomiR. (B) The level of miR-145 was increased in the cardiac fibroblasts (CFs) after treating with miR-145 agomiR. All results are expressed as mean ± standard error of the mean.*P < 0.05 versus the NC agomiR group. (PNG 588 kb)

High resolution image (TIF 118 kb)

Fig. S2

Effects of mitogen-activated protein kinase kinase kinase 3 (MAP3K3) overexpression or knockdown in cardiac fibroblasts (CFs). (A) The level of MAP3K3 was increased by MAP3K3 overexpression. (B) The level of MAP3K3 was increased by MAP3K3 knockdown. N = 6 for each group. All results are expressed as mean ± standard error of the mean.*P < 0.05 versus the Ad-GFP group. (PNG 487 kb)

High resolution image (TIF 54 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Hu, J., Wang, W. et al. MircroRNA-145 Attenuates Cardiac Fibrosis Via Regulating Mitogen-Activated Protein Kinase Kinase Kinase 3. Cardiovasc Drugs Ther 37, 655–665 (2023). https://doi.org/10.1007/s10557-021-07312-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-021-07312-w

Keywords

Search

Navigation