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

Abstract

Folmes CD, Wagg CS, Shen M, Clanachan AS, Tian R, Lopaschuk GD. Suppression of 5Ј-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts. Am J Physiol Heart Circ Physiol 297: H313-H321, 2009. First published May 8, 2009 doi:10.1152/ajpheart.01298.2008.-Activation of 5Ј-AMP-activated protein kinase (AMPK) may benefit the heart during ischemia-reperfusion by increasing energy production. While AMPK stimulates glycolysis, mitochondrial oxidative metabolism is the major source of ATP production during reperfusion of ischemic hearts. Stimulating AMPK increases mitochondrial fatty acid oxidation, but this is usually accompanied by a decrease in glucose oxidation, which can impair the functional recovery of ischemic hearts. To examine the relationship between AMPK and cardiac energy substrate metabolism, we subjected isolated working mouse hearts expressing a dominant negative (DN) ␣2-subunit of AMPK (AMPK-␣2 DN) to 20 min of global no-flow ischemia and 40 min of reperfusion with Krebs-Henseleit solution containing 5 mM [U-14 C]glucose, 0.4 mM [9, 10-3 H]palmitate, and 100 U/ml insulin. AMPK-␣2 DN hearts had reduced AMPK activity at the end of reperfusion (82 Ϯ 9 vs. 141 Ϯ 7 pmol ⅐ mg Ϫ1 ⅐ min Ϫ1 ) with no changes in high-energy phosphates. Despite this, AMPK-␣2 DN hearts had improved recovery of function during reperfusion (14.9 Ϯ 0.8 vs. 9.4 Ϯ 1.4 beats ⅐ min Ϫ1 ⅐ mmHg ⅐ 10 Ϫ3 ). During reperfusion, fatty acid oxidation provided 44.0 Ϯ 2.8% of total acetyl-CoA in AMPK-␣2 DN hearts compared with 55.0 Ϯ 3.2% in control hearts. Since insulin can inhibit both AMPK activation and fatty acid oxidation, we also examined functional recovery in the absence of insulin. Functional recovery was similar in both groups despite a decrease in AMPK activity and a decreased reliance on fatty acid oxidation during reperfusion (66.4 Ϯ 9.4% vs. 85.3 Ϯ 4.3%). These data demonstrate that the suppression of cardiac AMPK activity does not produce an energetically compromised phenotype and does not impair, but may in fact improve, the recovery of function after ischemia.ischemia-reperfusion; fatty acid oxidation; glycolysis; glucose oxidation MYOCARDIAL ISCHEMIA OCCURS when the oxygen requirement of the heart exceeds the oxygen supplied via the coronary circulation and is a devastating cause of morbidity and mortality worldwide. A contributing factor to ischemia-reperfusion (I/R) injury is the type of energy substrate used by the heart during and after ischemia (34,36,48). The majority of the energy requirement of the normal well-perfused heart is met by the oxidation of fatty acids, with the remainder coming from the oxidation of carbohydrates (34,36,48). However, during ischemia, mitochondrial oxidative metabolism is suppressed,

Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes

“…In hearts from AMPK dominate negative mutant of the α2 subunit (DNα2) of mice showed an actual increase in cardiac functional recovery during reperfusion after ischemia (Lopaschuk, 2008). Moreover, suppression of cardiac AMPK activity did not affect baseline cardiac function but may in fact improve the recovery of cardiac function after ischemia (Folmes et al, 2009). These seemingly controversial results may due to AMPK activation during ischemia not only has the potential to increase glucose uptake and glycolysis promoting energy supply to the heart but also has the potential to increase fatty acid oxidation, which by suppressing glucose oxidation can increase proton production and decrease cardiac function (Lopaschuk, 2008).…”

AMP-Activated Protein Kinase Regulation and Biological Actions in the Heart

“…125, 126 However, not all studies have documented a protective function of the AMPK pathway during ischemia. 127 …”

The Outcome of Renal Ischemia-Reperfusion Injury Is Unchanged in AMPK-β1 Deficient Mice

“…In the ischemic heart the effect of AMPK activation is reported to be beneficial by preventing post-ischemic cardiac dysfunction, apoptosis, and injury [3], [4], [5], [6]. These studies, however, have been contradicted by others, which showed that activation of AMPK in the ischemic heart has either no effect [7] or increases apoptosis [8]. Contrasting with the heart, activation of AMPK in the ischemic brain appears to worsen injury [9], [10], [11].…”