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

authors

  • CUADRADO BERROCAL, IRENE
  • GOMEZ GAVIRO, MARIA VICTORIA
  • BENITO, YOLANDA
  • BARRIO, ALICIA
  • BERMEJO, JAVIER
  • FERNÁNDEZ SANTOS, MARÍA EUGENIA
  • SÁNCHEZ, PEDRO L.
  • DESCO MENENDEZ, MANUEL
  • FERNÁNDEZ AVILÉS, FRANCISCO
  • FERNÁNDEZ VELASCO, MARÍA
  • BOSCA, LISARDO
  • DE LAS HERAS, BEATRIZ

publication date

  • February 2015

start page

  • 428

end page

  • 439

issue

  • 4

volume

  • 93

international standard serial number (ISSN)

  • 0006-2952

electronic international standard serial number (EISSN)

  • 1873-2968

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-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.

keywords

  • ischemia-reperfusion injury; nf-kappa-b; myocardial infarct size; therapeutic target; cardiac-function; protein-kinase; activation; heart; inhibition; inflammation