What is the clinical evidence from this study?

Study design: Other. Population: Myocardial ischemia and reperfusion. Intervention: Kinase dead (KD) mutation of AMPK vs. Wild-type (WT) littermates. Primary outcome: Glucose uptake and left ventricular contractile function recovery.

August 16, 2004Journal of Clinical Investigation725 citationsOpen Access

AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury

RRRaymond R. Russell JLJi Li DCDavid Coven

Key Result

In a transgenic mouse model, AMPK deficiency impaired ischemic glucose uptake and glycolysis, leading to significantly worse recovery of left ventricular contractile function and increased apoptosis.

Structured PICO

Population

Male transgenic mice expressing a kinase dead (KD) form of AMPK and wild-type littermates subjected to low-flow ischemia and reperfusion.

Exposure

Long-term inhibition of AMPK activity via transgenic expression of a kinase dead (KD) form of the enzyme (K45R α2 mutation).

Comparator

Wild-type (WT) littermate mice.

Outcome

Metabolic and functional responses to low-flow myocardial ischemia and postischemic reperfusion in vitro (including glucose uptake, glycolysis, fatty acid oxidation, and left ventricular contractile function).surrogate

AMPK plays a critical protective role during myocardial ischemia and reperfusion by activating glucose uptake and glycolysis, thereby limiting cardiac dysfunction, injury, and apoptosis.

Limitations

Measurements of total ATP in freeze-clamped hearts do not exclude the possibility that key subcellular pools of ATP might be more compromised in the KD hearts.
Glycogen replenishment was estimated from concentrations in different groups of mice, and studies designed to examine rates of glycogen synthesis are necessary.
Whether or not enhanced activation of AMPK might be cardioprotective in this setting remains to be proven.

Abstract

AMP-activated protein kinase (AMPK) is an important regulator of diverse cellular pathways in the setting of energetic stress.Whether AMPK plays a critical role in the metabolic and functional responses to myocardial ischemia and reperfusion remains uncertain.We examined the cardiac consequences of long-term inhibition of AMPK activity in transgenic mice expressing a kinase dead (KD) form of the enzyme.The KD mice had normal fractional shortening and no heart failure, cardiac hypertrophy, or fibrosis, although the in vivo left ventricular (LV) dP/dt was lower than that in WT hearts.During low-flow ischemia and postischemic reperfusion in vitro, KD hearts failed to augment glucose uptake and glycolysis, although glucose transporter content and insulin-stimulated glucose uptake were normal.KD hearts also failed to increase fatty acid oxidation during reperfusion.Furthermore, KD hearts demonstrated significantly impaired recovery of LV contractile function during postischemic reperfusion that was associated with a lower ATP content and increased injury compared with WT hearts.Caspase-3 activity and TUNEL-staining were increased in KD hearts after ischemia and reperfusion.Thus, AMPK is responsible for activation of glucose uptake and glycolysis during low-flow ischemia and plays an important protective role in limiting damage and apoptotic activity associated with ischemia and reperfusion in the heart.Nonstandard abbreviations used: acetyl-CoA carboxylase (ACC); 5-aminoimidazole-4-carboxamide-1--4-ribofuranoside (AICAR); AMP-activated protein kinase (AMPK); carnitine palmitoyltransferase-1 (CPT-1); kinase dead (KD); left ventricular (LV); LV developed pressure (LVDP); 6-phosphofructo-2-kinase (PFK-2).

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