期刊
BIOCHEMICAL PHARMACOLOGY
卷 93, 期 4, 页码 428-439出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2014.12.011
关键词
Labdane diterpenes; Ischemia/reperfusion injury; Heart; Apoptosis; Cardioprotection
资金
- Ministerio de Economia y Competitividad [BFU2011-24760, SAF2014-52492, IPT2012-1331-60000]
- Comunidad de Madrid [S2010/BMD-2378]
- Red Cardiovascular (RIC) [RD06/0014/0006]
- Santander-UCM [RD12/0042/0019, 0001, RD12/0042/0001, PR6/13-18857]
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas - Instituto de Salud Carlos III
- FEBS fellowship
- Intraeuropean Marie Curie fellowship [EIF 275885]
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-1 alpha, survival pathways and inhibition of NF-kappa B 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-1 alpha 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. (C) 2014 Elsevier Inc. All rights reserved.
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