Maturation of fatty acid oxidation in the newborn rabbit heart

Fatty acid oxidation dramatically increases secondary to a decreased acetyl CoA carboxylase (ACC) activity in 7-day compared to 1-day old rabbit hearts. The mechanism responsible for this rapid maturation of fatty acid oxidation and decreased ACC activity remain poorly understood. I hypothesized that increased 5' AMP-activated protein kinase (AMPK) activity is responsible for the decreased ACC activity in 7-day old hearts. To test this hypothesis, hearts from 1-day and 7-day old rabbits were used to characterize AMPK activity and abundance. Immunoblot analysis revealed that AMPK is present in both 1-day and 7-day old hearts. AMPK abundance was significantly upregulated in 7-day compared to 1-day old heart. Moreover, AMPK activity measured in Langendorff perfused hearts increased from 510 +/- 47 to 792 +/- 38 pmol/min/mg protein (p < 0.05) in 1-day and 7-day old hearts, respectively. This was paralleled by a decrease in ACC activity in 7-day compared to 1-day old hearts. Furthermore, fatty acid oxidation increased from 14 +/- 3 to 32 +/- 5 nmol/min/g dry (p < 0.05), in 1 day and 7-day old hearts, respectively.;AICAR (200 muM), a cell permeable nucleoside, stimulated AMPK activity and fatty acid oxidation in 7-day old hearts. Iodotubercidin (50 mum), an AMPK inhibitor, however, decreased fatty acid oxidation compared to controls. AMPK activity was positively correlated with fatty acid oxidation. Moreover, in reperfused-ischemic hearts, iodotubercidin (50 muM) significantly decreased AMPK activity and fatty acid oxidation compared to controls. In addition, hearts treated with iodotubercidin showed a significant improvement in functional recovery [92 +/- 4 vs 52 +/- 3%, (p < 0.05) in iodotubercidin and control hearts, respectively] during reperfusion.;In summary this study demonstrates that AMPK is important in the maturation and regulation of fatty acid oxidation in newborn hearts. Moreover, AMPK inhibitors improved functional recovery during reperfusion following ischemia in 7-day old hearts. If AMPK inhibitors improve functional recovery in the clinical setting of myocardial ischemia, they may be novel therapeutics in the treatment of ischemic heart disease.