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(Hypertension. 2004;44:662.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Mechanisms for Increased Glycolysis in the Hypertrophied Rat Heart

Luigino Nascimben; Joanne S. Ingwall; Beverly H. Lorell; Ilka Pinz; Vera Schultz; Keith Tornheim; Rong Tian

From the NMR Laboratory for Physiological Chemistry (L.N., J.S.I., I.P., R.T.), Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School; the Cardiovascular Division (B.H.L.), Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School; and the Department of Biochemistry and the Diabetes and Metabolism Unit (K.T.), Boston University School of Medicine, Boston, Mass.

Correspondence to Luigino Nascimben, MD, PhD, NMR Laboratory for Physiological Chemistry, Brigham and Women’s Hospital, 221 Longwood Ave, Room 252, Boston, MA 02115. E-mail lnascimben{at}partners.org.bwh.harvard.edu

Glycolysis increases in hypertrophied hearts but the mechanisms are unknown. We studied the regulation of glycolysis in hearts with pressure-overload LV hypertrophy (LVH), a model that showed marked increases in the rates of glycolysis (by 2-fold) and insulin-independent glucose uptake (by 3-fold). Although the V_max of the key glycolytic enzymes was unchanged in this model, concentrations of free ADP, free AMP, inorganic phosphate (P_i), and fructose-2,6-bisphosphate (F-2,6-P₂), all activators of the rate-limiting enzyme phosphofructokinase (PFK), were increased (up to 10-fold). Concentrations of the inhibitors of PFK, ATP, citrate, and H⁺ were unaltered in LVH. Thus, our findings show that increased glucose entry and activation of the rate-limiting enzyme PFK both contribute to increased flux through the glycolytic pathway in hypertrophied hearts. Moreover, our results also suggest that these changes can be explained by increased intracellular free [ADP] and [AMP], due to decreased energy reserve in LVH, activating the AMP-activated protein kinase cascade. This, in turn, results in enhanced synthesis of F-2,6-P₂ and increased sarcolemma localization of glucose transporters, leading to coordinated increases in glucose transport and activation of PFK.

Key Words: cardiac function • hypertrophy • protein kinases • cardiac metabolism • cyclic AMP

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