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

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.

journal_name

Basic Res Cardiol

journal_title

Basic research in cardiology

authors

Mendieta G,Ben-Aicha S,Casani L,Badimon L,Sabate M,Vilahur G

doi

10.1007/s00395-019-0760-z

subject

Has Abstract

pub_date

2019-11-28 00:00:00

pages

2

issue

1

eissn

0300-8428

issn

1435-1803

pii

10.1007/s00395-019-0760-z

journal_volume

115

pub_type

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