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- Title
Localizing extracellular signal–regulated kinase (ERK) in pharmacological preconditioning's trigger pathway.
- Authors
Philipp, Sebastian; Critz, Stuart D.; Lin Cui; Solodushko, Viktoriya; Cohen, Michael V.; Downey, James M.
- Abstract
Acetylcholine (ACh) and opioid receptor agonists trigger the preconditioned phenotype through sequential activation of the epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3-K), Akt, and nitric oxide synthase (NOS), and opening of mitochondrial (mito) KATP channels with the generation of reactive oxygen species (ROS). Although extracellular signal–regulated kinase (ERK) has recently been reported to be part of this pathway, its location has not been determined. To address this issue, we administered a 5–min pulse of ACh (550 µM) prior to 30 min of ischemia in isolated rabbit hearts. It reduced infarction from 30.4 ± 2.2% of the risk zone in control hearts to 12.3 ± 2.8% and co–administration of the MEK, and, therefore, downstream ERK inhibitor U0126 abolished protection (29.1 ± 4.6% infarction) con.rming ERK's involvement. MitoKATP opening was monitored in adult rabbit cardiomyocytes by measuring ROS production with MitoTracker Red. ROS production was increased by each of three G protein–coupled agonists: ACh (250 µM), bradykinin (BK) (500 nM), and the δ-opioid agonist DADLE (20 nM). Co–incubation with the MEK inhibitors U0126 (500 nM) or PD 98059 (10 µM) blocked the increased ROS production seen with all three agonists. Direct activation of its receptor by EGF increased ROS production and PD 98059 blocked that increase, thus placing ERK downstream of the EGF receptor. Desferoxamine (DFO) which opens mitoKATP through direct activation of NOS also increased ROS. PD 98059 could not block DFO–induced ROS production, placing ERK upstream of NOS. In isolated hearts, ACh caused phosphorylation of both Akt and ERK. U0126 blocked phosphorylation of ERK but not of Akt. The PI3–K inhibitor wortmannin blocked both. Together these data indicate that ERK is located between Akt and NOS.
- Subjects
ACETYLCHOLINE; CHOLINE; NEUROTRANSMITTERS; CHEMICAL reactions; OPIOID receptors; MEMBRANE proteins; ISCHEMIA
- Publication
Basic Research in Cardiology, 2006, Vol 101, Issue 2, p159
- ISSN
0300-8428
- Publication type
Article
- DOI
10.1007/s00395-005-0566-z