Skip to main content
SpringerLink
Log in

Transient gene therapy using cell cycle factors reverses renin–angiotensin–aldosterone system activation in heart failure rat model

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The loss of cardiomyocytes after myocardial infarction (MI) leads to heart failure. Recently, we demonstrated that transient overexpression of 4 cell cycle factors (4F), using a polycistronic non-integrating lentivirus (TNNT2-4F-NIL) resulted in significant improvement in cardiac function in a rat model of MI. Yet, it is crucial to demonstrate the reversal of the heart failure-related pathophysiological manifestations, such as renin–angiotensin–aldosterone system activation (RAAS). To assess that, Fisher 344 rats were randomized to receive TNNT2-4F-NIL or control virus seven days after coronary occlusion for 2 h followed by reperfusion. 4 months after treatment, N-terminal pro-brain natriuretic peptide, plasma renin activity, and aldosterone levels returned to the normal levels in rats treated with TNNT2-4F-NIL but not in vehicle-treated rats. Furthermore, the TNNT2-4F-NIL-treated group showed significantly less liver and kidney congestion than vehicle-treated rats. Thus, we conclude that in rat models of MI, TNNT2-4F-NIL reverses RAAS activation and subsequent systemic congestion.

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

Similar content being viewed by others

Abbreviations

CMs:

Cardiomyocytes

MI:

Myocardial infarction

RAAS:

Renin–angiotensin–aldosterone system

4F:

4 Cell cycle factors: cyclin B1, CDK1, cyclin D1, and CDK4

TNNT2:

Cardiac troponin-2

NIL:

Non-integrating lentivirus

OCT:

Optimal cutting temperature compound

NT-ProBNP:

N-terminal pro-brain natriuretic peptide

OD:

Optical density

PRA:

Plasma renin activity

ALD:

Aldosterone

H&E:

Hematoxylin and eosin

PAS:

Periodic acid–Schiff

PTC:

Peritubular capillaries

References

  1. Pasumarthi KBS, Field LJ (2002) Cardiomyocyte cell cycle regulation. Circ Res 90(10):1044–1054. https://doi.org/10.1161/01.RES.0000020201.44772.67

    Article  CAS  PubMed  Google Scholar 

  2. Thygesen K et al (2018) Fourth universal definition of myocardial infarction. Circulation 138(20):e618–e651. https://doi.org/10.1161/CIR.0000000000000617

    Article  PubMed  Google Scholar 

  3. Parmley WW (1985) Pathophysiology of congestive heart failure. Am J Cardiol 56(2):A7–A11. https://doi.org/10.1016/0002-9149(85)91199-3

    Article  Google Scholar 

  4. Unger T, Li J (2004) The role of the renin-angiotensin-aldosterone system in heart failure. J Renin Angiotensin Aldosterone Syst 5(Suppl 1):S7-10. https://doi.org/10.3317/jraas.2004.024

    Article  CAS  PubMed  Google Scholar 

  5. Salama ABM, Gebreil A, Mohamed TMA, Abouleisa RRE (2021) Induced cardiomyocyte proliferation: a promising approach to cure heart failure. Int J Mol Sci. https://doi.org/10.3390/ijms22147720

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bolli R, Solankhi M, Tang XL, Kahlon A (2022) Cell therapy in patients with heart failure: a comprehensive review and emerging concepts. Cardiovasc Res 118(4):951–976. https://doi.org/10.1093/cvr/cvab135

    Article  CAS  PubMed  Google Scholar 

  7. Mohamed TMA et al (2018) Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell 173(1):104-116.e12. https://doi.org/10.1016/j.cell.2018.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Abouleisa RRE et al (2022) Transient cell cycle induction in cardiomyocytes to treat subacute ischemic heart failure. Circulation. https://doi.org/10.1161/circulationaha.121.057641

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chow SL et al (2017) Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American heart association. Circulation 135(22):e1054–e1091. https://doi.org/10.1161/CIR.0000000000000490

    Article  CAS  PubMed  Google Scholar 

  10. Tomaschitz A, Pilz S, Ritz E, Meinitzer A, Boehm BO, März W (2010) Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Eur Heart J 31(10):1237–1247. https://doi.org/10.1093/eurheartj/ehq019

    Article  CAS  PubMed  Google Scholar 

  11. Sealey JE (1991) Plasma renin activity and plasma prorenin assays. Clin Chem 37(10):1811–1819. https://doi.org/10.1093/clinchem/37.10.1811

    Article  CAS  PubMed  Google Scholar 

  12. Hartman D, Sagnella GA, Chesters CA, MacGregor GA (2004) Direct renin assay and plasma renin activity assay compared. Clin Chem 50(11):2159–2161. https://doi.org/10.1373/clinchem.2004.033654

    Article  CAS  PubMed  Google Scholar 

  13. Hartupee J, Mann DL (2017) Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol 14(1):30–38. https://doi.org/10.1038/nrcardio.2016.163

    Article  CAS  PubMed  Google Scholar 

  14. Salah K et al (2019) Prognosis and NT-proBNP in heart failure patients with preserved versus reduced ejection fraction. Heart 105(15):1182. https://doi.org/10.1136/heartjnl-2018-314173

    Article  CAS  PubMed  Google Scholar 

  15. Yancy CW et al (2017) 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines and the heart failure society of America. Circulation 136(6):e137–e161. https://doi.org/10.1161/cir.0000000000000509

    Article  PubMed  Google Scholar 

  16. Heidenreich PA et al (2022) 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Am Coll Cardiol. https://doi.org/10.1016/j.jacc.2021.12.012

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sayer G, Bhat G (2014) The renin-angiotensin-aldosterone system and heart failure. Cardiol Clin. https://doi.org/10.1016/j.ccl.2013.09.002

    Article  PubMed  Google Scholar 

  18. Jia G, Aroor AR, Hill MA, Sowers JR (2018) Role of renin-angiotensin-aldosterone system activation in promoting cardiovascular fibrosis and stiffness. Hypertension 72(3):537–548. https://doi.org/10.1161/HYPERTENSIONAHA.118.11065

    Article  CAS  PubMed  Google Scholar 

  19. Bakogiannis C et al (2019) A translational approach to the renin-angiotensin-aldosterone system in heart failure. Ann Res Hosp 3:11

    Article  Google Scholar 

  20. Koitabashi N, Kass DA (2012) Reverse remodeling in heart failure—mechanisms and therapeutic opportunities. Nat Rev Cardiol 9(3):147–157. https://doi.org/10.1038/nrcardio.2011.172

    Article  CAS  Google Scholar 

  21. Reis Filho JRDAR, Cardoso JN, Cardoso CMDR, Pereira-Barretto AC (2015) Reverse cardiac remodeling: a marker of better prognosis in heart failure. Arq Bras Cardiol. https://doi.org/10.5935/abc.20150025

    Article  PubMed  Google Scholar 

  22. Hagen MK et al (2009) Diet with isolated soy protein reduces oxidative stress and preserves ventricular function in rats with myocardial infarction. Nutr Metab Cardiovasc Dis 19(2):91–97. https://doi.org/10.1016/j.numecd.2008.03.001

    Article  CAS  PubMed  Google Scholar 

  23. Zornoff LAM, Paiva SAR, Minicucci MF, Spadaro J (2009) Infarto do miocárdio experimental em ratos: análise do modelo. Arq Bras Cardiol 93(4):434–440. https://doi.org/10.1590/s0066-782x2009001000018

    Article  PubMed  Google Scholar 

  24. Cops J, Haesen S, De Moor B, Mullens W, Hansen D (2019) Current animal models for the study of congestion in heart failure: an overview. Heart Fail Rev 24(3):387–397. https://doi.org/10.1007/s10741-018-9762-4

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

TMAM is supported by NIH Grants R01HL147921 and P30GM127607 and American Heart Association Grant 16SDG29950012. RB is supported by NIH Grant HL-78825.

Author information

Authors and Affiliations

  1. Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA

    Abou Bakr M. Salama, Riham R. E. Abouleisa, Qinghui Ou, Xian-Liang Tang, Ahmad Gebreil, Muzammil Dastagir, Fareeha Abdulwali, Roberto Bolli & Tamer M. A. Mohamed

  2. Department of Cardiology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

    Abou Bakr M. Salama

  3. Department of Cardiac Surgery, University of Verona, Verona, Italy

    Abou Bakr M. Salama

  4. Department of Pathology, Faculty of Medicine, Suez University, Ismailia, Egypt

    Nashwah Alhariry

  5. Department of Electron Microscopy, Theodor Bilharz Research Institute, Imbaba Giza, Egypt

    Sarah Hassan & Tamer M. A. Mohamed

  6. Department of Bioengineering, University of Louisville, Louisville, KY, USA

    Abou Bakr M. Salama, Riham R. E. Abouleisa, Qinghui Ou, Xian-Liang Tang, Nashwah Alhariry, Sarah Hassan, Ahmad Gebreil, Muzammil Dastagir, Fareeha Abdulwali, Roberto Bolli & Tamer M. A. Mohamed

  7. Diabetes and Obesity Center, Department of Medicine, Envirome Institute, University of Louisville, Louisville, KY, USA

    Abou Bakr M. Salama, Riham R. E. Abouleisa, Qinghui Ou, Xian-Liang Tang, Nashwah Alhariry, Sarah Hassan, Ahmad Gebreil, Muzammil Dastagir, Fareeha Abdulwali, Roberto Bolli & Tamer M. A. Mohamed

  8. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA

    Abou Bakr M. Salama, Riham R. E. Abouleisa, Qinghui Ou, Xian-Liang Tang, Nashwah Alhariry, Sarah Hassan, Ahmad Gebreil, Muzammil Dastagir, Fareeha Abdulwali, Roberto Bolli & Tamer M. A. Mohamed

  9. Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK

    Tamer M. A. Mohamed

  10. Institute of Molecular Cardiology, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA

    Tamer M. A. Mohamed

Authors
  1. Abou Bakr M. Salama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Riham R. E. Abouleisa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qinghui Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xian-Liang Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nashwah Alhariry
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sarah Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ahmad Gebreil
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Muzammil Dastagir
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fareeha Abdulwali
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roberto Bolli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tamer M. A. Mohamed
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by ABMS, RREA, QO, XLT, NA, SH, AG, MD, and FA. The first draft of the manuscript was written by ABMS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Tamer M. A. Mohamed.

Ethics declarations

Conflict of interest

TMAM holds equities in Tenaya Therapeutics. The other authors report no conflict.

Research involving human and animals rights

No animal studies were carried out by the authors for this article. Plasma and tissue samples were available from previous studies.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salama, A.B.M., Abouleisa, R.R.E., Ou, Q. et al. Transient gene therapy using cell cycle factors reverses renin–angiotensin–aldosterone system activation in heart failure rat model. Mol Cell Biochem 478, 1245–1250 (2023). https://doi.org/10.1007/s11010-022-04590-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-022-04590-2

Keywords

Search

Navigation