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1 Medicine, Brigham and Women's Hospital, Boston, MA, USA; Medicine, Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: jbalschi{at}rics.bwh.harvard.edu.
The hypothesis was tested that hypoxia increases AMPK activity independently of AMP concentration ([AMP]) in the heart. In isolated perfused rat hearts cytosolic [AMP] was changed from 0.2 to 16 µM using metabolic inhibitors during both normal oxygenation (95% O2 /5% CO2, normoxia) and limited oxygenation (95% N2/5% CO2, hypoxia). Total AMPK activity measured in vitro ranged from 2 to 40 pmol x min-1 x mg protein-1 in normoxic hearts and from 5 to 55 pmol x min-1 x mg protein-1 in hypoxic hearts. The dependence of the in vitro total AMPK activity on the in vivo cytosolic [AMP] was determined by fitting the measurements from individual hearts to a hyperbolic equation. The [AMP] resulting in half maximal (A0.5) total AMPK activity was 3 ± 1 µM for hypoxic hearts and 28 ± 13 µM for normoxic hearts. The A0.5 for 
2 isoform AMPK activity was 2 ± 1 µM for hypoxic hearts and 13 ± 8 µM for normoxic hearts. Total AMPK activity correlated with the phosphorylation of the threonine-172 (Thr172) residue of the AMPK subunit. In potassium arrested hearts perfused with variable O2 content, subunit Thr172 phosphorylation increased at O2 
21% even though [AMP] was below 0.3 µM. Thus, hypoxia or O2 21% increased AMPK phosphorylation and activity independently of cytosolic [AMP]. The hypoxic increase in AMPK activity may result from either direct phosphorylation of Thr172 by an upstream kinase or by a reduction in the A0.5 for [AMP].
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