Molecular pathways involved in the cardioprotective effects of intravenous statin administration during ischemia
Por:
Mendieta, G, Ben-Aicha, S, Casani, L, Badimon, L, Sabate, M, Vilahur, G
Publicada:
1 ene 2020
Resumen:
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.
Filiaciones:
Mendieta, G:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Avda S Antoni Maria Claret 167, Barcelona 08025, Spain
UB, Sch Med, Barcelona, Spain
UB, Hosp Clin, IDIBAPS, Cardiovasc Inst, Barcelona, Spain
Ben-Aicha, S:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Avda S Antoni Maria Claret 167, Barcelona 08025, Spain
UB, Sch Med, Barcelona, Spain
Casani, L:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Avda S Antoni Maria Claret 167, Barcelona 08025, Spain
Inst Salud Carlos III, CIBERCV, Madrid, Spain
Badimon, L:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Avda S Antoni Maria Claret 167, Barcelona 08025, Spain
Inst Salud Carlos III, CIBERCV, Madrid, Spain
Autonomous Univ Barcelona UAB, Barcelona, Spain
Sabate, M:
UB, Hosp Clin, IDIBAPS, Cardiovasc Inst, Barcelona, Spain
Vilahur, G:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Avda S Antoni Maria Claret 167, Barcelona 08025, Spain
Inst Salud Carlos III, CIBERCV, Madrid, Spain
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