p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

Abstract

Clanachan AS. p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5Ј-AMP-activated protein kinase. Am J Physiol Heart Circ Physiol 292: H1978 -H1985, 2007. First published December 15, 2006; doi:10.1152/ajpheart.01121.2006.-Adenosineinduced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5Ј-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 ϫ 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.adenosine; adenosine 5Ј-monophosphate-activated protein kinase; glycogen metabolism CARDIOPROTECTION INDUCED BY adenosine and the adenosine A 1 receptor agonist N 6 -cyclohexyladenosine may be related to their ability to stimulate glycogen synthesis and inhibit glycolysis and proton production during reperfusion following ischemia (7, 9). However, our laboratory has shown that in hearts stressed by transient ischemia, there is a loss of adenosineinduced cardioprotection (8), an effect consistent with the lower cardioprotective effectiveness of adenosine and adenosine mimetic agents in studies involving patients with coronary artery disease (24). Because this model of transient ischemia differs from ischemic preconditioning, in that the transient ischemia does not enhance the recovery of left ventricular (LV) function following severe ischemia (8), stressing by transient ischemia may provide a unique system in which to study the mechanisms underlying the loss of adenosine-induced cardioprotection observe...

Adiponectin Enhances IL-6 Production in Human Synovial Fibroblast via an AdipoR1 Receptor, AMPK, p38, and NF-κB Pathway

“…These effects were inhibited by araA, compound C and AdipoR1 siRNA, indicating the involvement of AdipoR1-AMPK-dependent p38 activation in adiponectin-mediated IL-6 induction. It has also reported that AMPK is downstream molecule of p38 in the control of myocardial glucose metabolism (41). In this study, we found that p38 inhibitor SB203580 cannot antagonized the adiponectin or AICAR-increased AMPK phosphorylation and kinase activity.…”

Suppression of 5′-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts

“…In addition, at the end of reperfusion, AMP-to-ATP ratios were similar between groups, an effect that agrees with the observed ratios at the end of reperfusion in AMPK-␣ 2 KO mice (7,53). Of interest is that glycogen levels in AMPK-␣ 2 DN hearts were elevated at the end of reperfusion in the presence of insulin, which correlates well with previous studies that demonstrated an inverse correlation between AMPK activity and glycogen content in both the heart (18,19) and skeletal muscle (3). This increase in glycogen content may be due to reduced phosphorylation of site 2 of glycogen synthase (20,50) or may be due to a greater shunting of glucose toward glycogen synthesis because of an inhibition of glycolysis (18).…”

Inhibition of p38 MAPK and AMPK restores adenosine-induced cardioprotection in hearts stressed by antecedent ischemia by altering glucose utilization

“…Glycolysis and glucose oxidation rates were measured directly from the simultaneous production of 3 H2O (liberated at the enolase step of glycolysis) and 14 CO2 (liberated at the level of pyruvate dehydrogenase complex and in the citric acid cycle), respectively, from [5-3 H]glucose and [U- 14 C]glucose, as described previously (8 Calculation of the rate of proton production arising from exogenous glucose metabolism. When glucose (from endogenous or exogenous sources) is metabolized by glycolysis and subsequently oxidized 1:1, with the associated synthesis and hydrolysis of ATP, the net production of protons is zero.…”

“…Furthermore, we have demonstrated that inhibition of p38 mitogen-activated protein kinase (MAPK) inhibits the activation of AMPK, attenuates the rates of glycolysis and H ϩ production, as well as relieving the suppression of glycogen synthesis (14). Whether this mechanism persists in stressed hearts during reperfusion following severe ischemia and translates into cardioprotection has yet to be determined.…”