Abstract:
:Attenuation of excessive rates of myocardial glycolysis limits proton production and Ca(2+) overload during reperfusion and improves recovery of post-ischemic left ventricular (LV) function. In order to elucidate mechanisms underlying glycolytic inhibition by adenosine (ADO), this study tested the hypothesis that the beneficial effects of ADO are due to Ser/Thr protein phosphatase (PP)-mediated inhibition of 5'-AMP-activated protein kinase (AMPK) and phosphofructokinase-2 (PFK-2). In isolated perfused working rat hearts subjected to global ischemia (GI) and reperfusion, ADO (500μmol/l), added 5min prior to the onset of GI and present throughout reperfusion, inhibits glycolysis and proton production during reperfusion and improves post-ischemic LV work. These metabolic effects of ADO are also evident during aerobic perfusion. Assays of glycolytic intermediates show that ADO-induced glycolytic inhibition occurs at the step catalyzed by PFK-1, an effect mediated by reduced activation of PFK-2 by AMPK. The PP1 and PP2A inhibitors, cantharidin (5μmol/l) or okadaic acid (0.1μmol/l), added 10min prior to ADO prevent ADO-induced inhibition of glycolysis and AMPK, as well as ADO-induced cardioprotection. ADO also inhibits p38 MAPK phosphorylation during reperfusion in a cantharidin-sensitive manner, and pharmacological inhibition of p38 MAPK (by SB202190, 10μmol/l) during reperfusion also reduces glycolysis and is cardioprotective. These results indicate that attenuation of glycolysis during reperfusion and cardioprotection can be achieved by inhibition of the stress kinases, AMPK and p38 MAPK.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Omar MA,Verma S,Clanachan ASdoi
10.1016/j.yjmcc.2012.03.014subject
Has Abstractpub_date
2012-06-01 00:00:00pages
1308-18issue
6eissn
0022-2828issn
1095-8584pii
S0022-2828(12)00123-Xjournal_volume
52pub_type
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