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

作者：Cuadrado Berrocal Irene; Gomez Gaviro Maria V; Benito Yolanda; Barrio Alicia; Bermejo Javier; Fernandez Santos Maria Eugenia; Sanchez Pedro L; Desco Manuel; Fernandez Aviles Francisco; Fernandez Velasco Maria; Bosca Lisardo^*; de las Heras Beatriz

来源：Biochemical Pharmacology, 2015, 93(4): 428-439.

DOI：10.1016/j.bcp.2014.12.011

• Labdane diterpenes
• Ischemia/reperfusion injury
• Heart
• Apoptosis
• Cardioprotection

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.

• 出版日期2015-2-15