Impaired p38 MAPK/HSP27 signaling underlies aging-related failure in opioid-mediated cardioprotection. J Mol Cell Cardiol 2007 May;42(5):972-80
Date
04/05/2007Pubmed ID
17407780Pubmed Central ID
PMC2497430DOI
10.1016/j.yjmcc.2007.02.011Scopus ID
2-s2.0-34247619761 (requires institutional sign-in at Scopus site) 72 CitationsAbstract
Cardioprotection and preconditioning mediated via G-protein-coupled receptors may be lost or impaired with advancing age, limiting ischemic tolerance and the ability to pharmacologically protect older hearts from ischemic injury. Our preliminary findings indicated a loss of delta-opioid receptor-mediated protection in aged vs. young mouse hearts, which may involve alterations in protective kinase signaling. In the present study, we tested the hypothesis that aging-related loss of opioid-triggered cardioprotection involves failure to activate p38 MAPK and its distal signaling targets. Langendorff-perfused hearts from young (10-14 weeks) or aged (24-26 months) C57 mice underwent 25-min ischemia and 45-min reperfusion in the presence or absence of 1 micromol/l DPDPE (delta-opioid agonist) or 1 micromol/l anisomycin (activator of p38 MAPK), and functional recovery and protein activation/phosphorylation were assessed. Contractile recovery was similar in untreated young and aged hearts (50+/-2% and 53+/-5%, respectively), and was enhanced by DPDPE in young hearts only (67+/-3%). Immunoblot analysis revealed that DPDPE comparably activated or phosphorylated GRK2, Akt, ERK1/2 and p70S6 kinase in young and aged hearts, whereas aging abrogated the stimulatory effects of DPDPE on p38 MAPK and HSP27. Treatment with anisomycin elicited comparable activation of p38 MAPK and HSP27 in both young and aged hearts, coupled with a pronounced and equivalent cardioprotection in the two groups (73+/-3% and 77+/-2%, respectively), an effect abolished by the p38 MAPK inhibitor, SB203580. These data indicate that aging-related loss of delta-opioid-mediated cardioprotection involves failure to activate p38 MAPK and HSP27. Direct targeting of this pathway elicits comparable protection in both age groups.
Author List
Peart JN, Gross ER, Headrick JP, Gross GJMESH terms used to index this publication - Major topics in bold
AgingAnimals
Anisomycin
Cardiotonic Agents
Enkephalin, D-Penicillamine (2,5)-
G-Protein-Coupled Receptor Kinase 2
HSP27 Heat-Shock Proteins
Heart
Heat-Shock Proteins
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Myocardium
Phosphorylation
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases, 70-kDa
Signal Transduction
beta-Adrenergic Receptor Kinases
p38 Mitogen-Activated Protein Kinases
