Abstract 1130: Inhibition of p38 MAPK Restores the Cardioprotective Effects of Adenosine in Stressed Hearts by Inhibiting AMPK and Glycolysis
p38 MAPK and 5′-AMP activated protein kinase (AMPK) are activated by metabolic stresses and are implicated in the regulation of glucose utilization, and ischemia-reperfusion (IR) injury. While adenosine (Ado) inhibits glycolytic flux (GF) and proton (H+) production in aerobic and reperfused hearts, it accelerates GF and H+ production in hearts stressed by transient ischemia by activating p38 MAPK and AMPK. This study tested the hypothesis that inhibition of p38 MAPK restores the cardioprotective effects of Ado in stressed hearts by preventing activation of AMPK and the acceleration of GF and H+ production. Isolated working rat hearts were perfused with Krebs solution (1.2 mM palmitate, 11 mM [3H/14C]glucose and 100 mU/L insulin). After 15 min of aerobic perfusion, hearts were stressed by two periods of transient ischemia (10 min I / 5 min R), prior to severe I (30 min) and R (30 min). Hearts were untreated, or were treated during IR with Ado (500 μM), the p38 MAPK inhibitor, SB202190 (10 μM), or their combination. LV work (Joules), rates (μmol/g dry wt/ min) of GF, glucose oxidation and H+ production as well as phosphorylation (ADU) of p38 MAPK and AMPK were similar among groups prior to R. Ado did not enhance recovery of LV work in stressed hearts during R. The phosphorylation of p38 MAPK and AMPK, rates of glucose metabolism and the extents of recovery of LV work were similar in untreated, Ado-treated, and SB202190-treated hearts. However, Ado, in combination with SB202190, increased recovery of LV work (from 0.30±15, n=8 to 0.81±0.08, n=7, P<0.05). Relative to Ado-treated hearts, treatment with a combination of SB202190 and Ado decreased the phosphorylation of p38 MAPK (0.48±0.10 vs 0.03±0.01, n=3, P<0.05) and AMPK (0.26±0.08 vs 0.00±0.00, P<0.05). This was accompanied by an attenuation of the rates of GF (1.51±0.40, n=7 vs 3.95±0.65, n=7, PM<0.05), and H+ production (2.12±0.76, n=7 vs 6.96±1.48, n=7, P<0.05), indicative of improved glucose metabolism compared with hearts treated with Ado alone. These data indicate that inhibition of p38 MAPK in Ado-treated hearts abolishes the subsequent phosphorylation of AMPK. This improves the coupling of glucose metabolism, and restores the cardioprotective effects of Ado in stressed hearts.