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Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/129376
Título

A labdane diterpene exerts ex vivo and in vivo cardioprotection against post-ischemic injury: Involvement of AKT-dependent mechanisms

AutorCuadrado-Berrocal, Irene; Fernández-Velasco, María ; Boscá, Lisardo ; Heras, Beatriz de las
Palabras claveLabdane diterpenes
Ischemia/reperfusion injury
Heart
Apoptosis
Cardioprotection
Fecha de publicación2015
EditorElsevier
CitaciónBiochemical Pharmacology 93(4): 428-439 (2015)
ResumenTherapeutic 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 30 min followed by 72 h reperfusion. DT1 (5 mg/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.
Descripciónet al.
Versión del editorhttp://dx.doi.org/10.1016/j.bcp.2014.12.011
URIhttp://hdl.handle.net/10261/129376
DOI10.1016/j.bcp.2014.12.011
ISSN0006-2952
E-ISSN1873-2968
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