Impaired p38 MAPK/HSP27 signaling underlies aging-related failure in opioid-mediated cardioprotection.
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.
Peart
Jason N
JN
Heart Foundation Research Center, Griffith University, Queensland, 9726, Australia. j.peart@griffith.edu.au
Gross
Eric R
ER
Headrick
John P
JP
Gross
Garretta J
GJ
D000375:Aging; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology*; D054769:G-Protein-Coupled Receptor Kinase 2; D055551:HSP27 Heat-Shock Proteins; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002316:Cardiotonic Agents; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D000841:Anisomycin; D020881:Enkephalin, D-Penicillamine (2,5)-; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C496568:GRK2 protein, mouse; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases