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Sacubitril/valsartan reverses cardiac structure and function in experimental model of hypertension-induced hypertrophic cardiomyopathy

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Abstract

This study evaluated the effect of sacubtril/valsartan on cardiac remodeling, molecular and cellular adaptations in experimental (rat) model of hypertension-induced hypertrophic cardiomyopathy. Thirty Wistar Kyoto rats, 10 healthy (control) and 20 rats with confirmed hypertension-induced hypertrophic cardiomyopathy (HpCM), were used for this study. The HpCM group was further subdivided into untreated and sacubitril/valsartan-treated groups. Myocardial structure and function were assessed using echocardiography, Langendorff’s isolated heart experiment, blood sampling and qualitative polymerase chain reaction. Echocardiographic examinations revealed protective effects of sacubitril/valsartan by improving left ventricular internal diameter in systole and diastole and fractional shortening. Additionally, sacubitril/valsartan treatment decreased systolic and diastolic blood pressures in comparison with untreated hypertensive rats. Moreover, sacubitril/valsartan treatment reduced oxidative stress and apoptosis (reduced expression of Bax and Cas9 genes) compared to untreated rats. There was a regular histomorphology of cardiomyocytes, interstitium, and blood vessels in treated rats compared to untreated HpCM rats which expressed hypertrophic cardiomyocytes, with polymorphic nuclei, prominent nucleoli and moderately dilated interstitium. In experimental model of hypertension-induced hypertrophic cardiomyopathy, sacubitril/valsartan treatment led to improved cardiac structure, haemodynamic performance, and reduced oxidative stress and apoptosis. Sacubitril/valsartan thus presents as a potential therapeutic strategy resulted in hypertension-induced hypertrophic cardiomyopathy.

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All data generated or analyzed during this study are included in this published article. Additional information could be obtained from the corresponding author.

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Acknowledgements

The authors are grateful to Katarina Virijević and Mihajlo Kokanović for sample handling and mRNA isolation.

Funding

This work was supported by the EU Horizon 2020 research and innovation programme below grant agreement Number 777204 (SILICOFCM). This work was supported by the European Union’s Horizon 2020 research and innovation programme SGABU (Grant agreement 952603). The Commission is not responsible for any use that may be made of the information it contains.The authors appreciatively acknowledge funding from the Ministry of Education, Science and Technological Development of the Republic of Serbia (Agreement Number 451-03-68/2022-14/200378 and 451‐03‐68/2022‐14/200107). The design of the study, data collection, analyses, interpretation of data, and drafting of the manuscript do not reflect the views and opinions of the funders.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Jovana Jeremic, Jovana Bradic, Isidora Milosavljevic, Nevena Jeremic & Tamara Nikolic Turnic

  2. Center of Excellence for Redox Balance Research, Cardiovascular and Metabolic Disorders, Kragujevac, Serbia

    Jovana Jeremic, Jovana Bradic, Isidora Milosavljevic, Ivan Srejovic, Vladimir Zivkovic, Nevena Jeremic, Tamara Nikolic Turnic & Vladimir Jakovljevic

  3. Federal Clinical Center for High Medical, Technologies Federal Health Biological Agency, Moscow, Russia

    Natalia Govoruskina

  4. Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000, Kragujevac, Serbia

    Ivan Srejovic, Vladimir Zivkovic & Vladimir Jakovljevic

  5. Department of Pharmacology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

    Ivan Srejovic, Vladimir Zivkovic & Stefani Bolevich

  6. I.M. Sechenov First Moscow State Medical University, Moscow, Russia

    Nevena Jeremic

  7. F.F. Erismann Institute of Public Health, N.A. Semashko Public Health and Healthcare Department, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

    Tamara Nikolic Turnic

  8. Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Irena Tanaskovic

  9. Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

    Stefani Bolevich

  10. Department of Human Pathology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

    Vladimir Jakovljevic & Sergey Bolevich

  11. Institute for Information Technologies Kragujevac, University of Kragujevac, Kragujevac, Serbia

    Marko N. Zivanovic, Dragana Seklic, Nevena Milivojevic & Jelena Grujic

  12. BioIRC - Bioengineering Research and Development Center, University of Kragujevac, Kragujevac, Serbia

    Marko N. Zivanovic & Nenad Filipovic

  13. Translational and Clinical Research Instutute, Faculty of Medical Sciences, Newcastle University and Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK

    Nduka Okwose, Guy MacGowan & Djordje G. Jakovljevic

  14. Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia

    Lazar Velicki

  15. Institute of Cardiovascular Diseases of Vojvodina, Sremska Kamenica, Serbia

    Lazar Velicki

  16. Faculty Research Centre (CSELS), Faculty of Health and Life Sciences, Institute for Health and Wellbeing (CSELS), Coventry University, London, UK

    Djordje G. Jakovljevic

  17. Faculty of Engineering, University of Kragujevac, Kragujevac, Serbia

    Nenad Filipovic

Authors
  1. Jovana Jeremic
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  2. Natalia Govoruskina
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Contributions

DGJ, JJ, JB, JG, NM, MNZ, NF: Study concept and design, JJ, IM, JG, DS, NF: Study Supervision, JJ, JB, IM, IV, VZ, NJ, TNT, SB, DS, NM, NG: Acquisition of data, JJ, NCO, IT, DGJ, SB, VJ, MNZ, DS, JG, VZ: Data analysis and interpretation of data, JJ, MNZ, NCO, DGJ, JB: Drafting of the manuscript, DGJ, JJ, NCO, GAM, LV, MNZ, NF: Critical revision of the manuscript, All authors approved the final version. DGJ and NF act as the guarantor and take responsibility for the content of the manuscript, including the data and analysis.

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Correspondence to Vladimir Jakovljevic.

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The protocol for this study was approved by the ethical committee for experimental animals’ well-being of the Faculty of Medical Sciences, University of Kragujevac, Serbia. All animals used in this study were sourced from the Institute for Medical Research, University of Belgrade, and written informed consent was obtained prior to use of the animals.

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Jeremic, J., Govoruskina, N., Bradic, J. et al. Sacubitril/valsartan reverses cardiac structure and function in experimental model of hypertension-induced hypertrophic cardiomyopathy. Mol Cell Biochem 478, 2645–2656 (2023). https://doi.org/10.1007/s11010-023-04690-7

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