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Molecular pathways involved in the cardioprotective effects of intravenous statin administration during ischemia

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Abstract

The success of therapies targeting myocardial reperfusion injury is limited, while the cardioprotective impact of mitigating ischemia-related damage remains less explored. We have recently shown in a pig model that the intravenous administration of a modified atorvastatin preparation during ischemia attenuates the rise of cardiac ischemia injury biomarkers. In the following study, we sought to investigate the mechanisms behind these ischemia-related cardioprotective effects. Ischemia was induced by 90 min total coronary balloon occlusion in pigs fed a normocholesterolemic regime. Fifteen minutes after the onset of ischemia, animals were randomized to receive intravenous atorvastatin preparation (IV-atorva) or vehicle. After ischemia animals were euthanized to assess the effect of IV-atorva treatment on gene and protein levels/activation of senescence-, apoptosis-, and cardioprotective/metabolic-related markers. Proof-of-concept studies were carried out in mice and rats in which treatments or vehicle were administered 15 min after initiation of ischemia induced by permanent coronary ligation. Western-blot analyses revealed that in the ischemic myocardium of IV-atorva-treated pigs, RhoA was inactivated, phosphorylation of p53 and caspase-3 was reduced and AMPK was activated with the consequent regulation of the mTOR/raptor-signaling pathway. IV-atorva-treated rats showed, as compared to vehicle, a significant reduction (60%) in scar size assessed at 1 month by histological staining, and mice studies demonstrated the causal involvement of AMPK activation in IV-atorva mediated cardioprotective effects. We demonstrate in pigs and rodents that prompt intravenous treatment with atorvastatin during ischemia limits cardiac cell death and reduces infarct size through AMPK signaling.

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Acknowledgements

We gratefully acknowledge the valuable help and support of M.A. Canovas, P. Catalina, and J. Moreno with animal handling and for the proper conduct of all the experimental and molecular work. This article is part of the PhD studies of G.Mendieta at the Medical School of the University of Barcelona and at the Cardiovascular Program ICCC.

Funding

This work was supported by the Fundació Investigació Marato TV3 #20154310 (to GV), Plan Nacional de Salud (PNS) [PGC2018-094025-B-I00 to GV and SAF2016-76819-R to LB] from the Spanish Ministry of Science and Innovation and funds FEDER “Una Manera de Hacer Europa”; and CIBERCV (to LB). We thank the support of the Generalitat of Catalunya (Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat, 2017 SGR 1480) and the Fundación Investigación Cardiovascular-Fundación Jesus Serra for their continuous support.

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Authors and Affiliations

  1. Cardiovascular Program-ICCC, Research Institute-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Avda. S. Antoni María Claret 167, 08025, Barcelona, Spain

    Guiomar Mendieta, Soumaya Ben-Aicha, Laura Casani, Lina Badimon & Gemma Vilahur

  2. School of Medicine, University of Barcelona (UB), Barcelona, Spain

    Guiomar Mendieta & Soumaya Ben-Aicha

  3. Cardiovascular Institute, Hospital Clínic, IDIBAPS, University of Barcelona (UB), Barcelona, Spain

    Guiomar Mendieta & Manel Sabate

  4. CIBERCV, Instituto Salud Carlos III, Madrid, Spain

    Laura Casani, Lina Badimon & Gemma Vilahur

  5. Cardiovascular Research Chair Autonomous University of Barcelona (UAB), Barcelona, Spain

    Lina Badimon

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  1. Guiomar Mendieta
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  2. Soumaya Ben-Aicha
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  3. Laura Casani
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  4. Lina Badimon
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  5. Manel Sabate
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  6. Gemma Vilahur
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Correspondence to Gemma Vilahur.

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Conflict of interest

LB and GV are the authors of the patent (PCT/EP2018/058158) that includes the use of statins for intravenous administration. The remaining authors have no conflict of interest.

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Mendieta, G., Ben-Aicha, S., Casani, L. et al. Molecular pathways involved in the cardioprotective effects of intravenous statin administration during ischemia. Basic Res Cardiol 115, 2 (2020). https://doi.org/10.1007/s00395-019-0760-z

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