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

  • Guiomar Mendieta
  • Soumaya Ben-Aicha
  • Laura Casani
  • Lina Badimon
  • Manel Sabate
  • Gemma VilahurEmail author
Original Contribution


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.


Myocardial ischemia Intravenous statin Cardioprotection Animal models AMPK 



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.


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.

Compliance with ethical standards

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.

Supplementary material

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Supplementary material 1 (TIFF 294 kb)
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Supplementary material 2 (TIFF 138 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Cardiovascular Program-ICCCResearch Institute-Hospital de la Santa Creu i Sant Pau, IIB-Sant PauBarcelonaSpain
  2. 2.School of MedicineUniversity of Barcelona (UB)BarcelonaSpain
  3. 3.Cardiovascular InstituteHospital Clínic, IDIBAPS, University of Barcelona (UB)BarcelonaSpain
  4. 4.CIBERCV, Instituto Salud Carlos IIIMadridSpain
  5. 5.Cardiovascular Research Chair Autonomous University of Barcelona (UAB)BarcelonaSpain

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