Anisomycin/p38 MAPK Activation Restores Cardioprotection in the Aged Heart

Abstract

Preconditioning mediated via G-protein coupled receptors is typically lost with advancing age. We previously reported untreated hearts from young (3 months) and aged C57/Bl6 mice (18 months) recovered similarly following ischemia and reperfusion. However, treatment with the delta-opioid receptor ligand, DPDPE (1μM), significantly improved recovery in young, but failed to alter recovery in aged hearts (Peart et al., FASEB Journal, 2005, 19 (5): A1563). Examination of post-receptor signaling through Western immunoblot analysis following acute opioid receptor activation revealed similar translocation of GRK2 along with phosphorylation of Akt, p42/44 MAPK and p70S6K in both young and aged hearts. However, while stimulation with DPDPE produced a pronounced phosphoylation of HSP27, a distal mediator of p38 MAPK, in the young hearts, phosphorylation was unchanged in aged hearts. Based on these findings, we sought to investigate the role of p38 MAPK in the age-related loss of opioid preconditioning. To this end, Langendorff-perfused hearts from young or aged C57 mice underwent 25 min ischemia and 45 min reperfusion in the presence or absence of 1μM anisomycin, an activator of p38 MAPK. Contractile recovery was paralleled in untreated young and aged hearts (50±1% and 53±5%, respectively). Importantly, anisomycin treatment elicited pronounced anti-ischemic protection, comparable in both young and aged hearts (73±3% and 76±2%, respectively. P<0.05 vs untreated). In summary, while anti-stunning effect of delta-opioid receptor activation is lost in the aged heart, exogenous activation of p38 MAPK maintains preconditioning in the aged. These results suggest a failure in post-receptor signalling upstream of p38 MAPK. This study was supported by NIH grant HL-08311 and AHA Postdoctoral Fellowship.