title: A labdane diterpene exerts ex vivo and in vivo cardioprotection against post-ischemic injury: involvement of AKT-dependent mechanisms.
abstract: Therapeutic approaches to protect the heart from ischemia/reperfusion (I/R) injury are an area of intense research, as myocardial infarction is a major cause of mortality and morbidity. Diterpenes are bioactive natural products with great therapeutic potential. In the present study, we have investigated the in vivo cardioprotective effects of a labdane diterpene (DT1) against cardiac I/R injury and the molecular mechanisms involved. DT1 attenuates post-ischemic injury via an AKT-dependent activation of HIF-1α, survival pathways and inhibition of NF-κB signaling. Myocardial infarction (MI) was induced in Wistar rats occluding the left coronary artery (LCA) for 30min followed by 72h reperfusion. DT1 (5mg/kg) was intravenously administered at reperfusion. In addition, we investigated the mechanisms of cardioprotection in the Langendorff-perfused model. Cardioprotection was observed when DT1 was administered after myocardial injury. The molecular mechanisms involved the activation of the survival pathway PDK-1, AKT and AMPK, a reduced phosphorylation of PKD1/2 and sustained HIF-1α activity, leading to increased expression of anti-apoptotic proteins and decreased caspase-3 activation. Pharmacological inhibition of AKT following MI and prior to DT1 challenge significantly decreased the cardioprotection afforded by DT1 therapy at reperfusion. Cardiac function after MI was significantly improved after DT1-treatment, as evidenced by hemodynamic recovery and decreased myocardial infarct size. These findings demonstrate an efficient in vivo cardioprotection by diterpene DT1 against I/R when administered at reperfusion, opening new therapeutic strategies as adjunctive therapy for the pharmacological management of I/R injury.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Cuadrado-Berrocal
authors.affiliation: Servicio de Cardiología, Instituto de Investigación Sanitaria Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain; Unidad de Medicina y Cirugía Experimental, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Departamento de Bioingeniería e Ingeniería Aerospacial, Universidad Carlos III, Madrid, Spain.
authors.forename: María V
authors.initials: MV
authors.lastname: Gómez-Gaviro
authors.affiliation: Servicio de Cardiología, Instituto de Investigación Sanitaria Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Benito
authors.affiliation: Servicio de Cardiología, Instituto de Investigación Sanitaria Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Barrio
authors.affiliation: Servicio de Cardiología, Instituto de Investigación Sanitaria Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Bermejo
authors.affiliation: Servicio de Cardiología, Instituto de Investigación Sanitaria Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Fernández-Santos
authors.affiliation: Servicio de Cardiología, Instituto de Investigación Sanitaria Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Sánchez
authors.affiliation: Unidad de Medicina y Cirugía Experimental, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Departamento de Bioingeniería e Ingeniería Aerospacial, Universidad Carlos III, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Desco
authors.affiliation: Servicio de Cardiología, Instituto de Investigación Sanitaria Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández-Avilés
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Instituto de Investigación Hospital Universitario La PAZ, IDIPAZ, Paseo de la Castellana, 28029 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Velasco
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Instituto de Investigación Hospital Universitario La PAZ, IDIPAZ, Paseo de la Castellana, 28029 Madrid, Spain. Electronic address: lbosca@iib.uam.es.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain. Electronic address: lasheras@ucm.es.
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Las Heras
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002316:Cardiotonic Agents; D004224:Diterpenes; C433017:labdane; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; Cardioprotection; Heart; Ischemia/reperfusion injury; Labdane diterpenes