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UDP N-Acetyl Glucosamine

Pyruvate

Glucose-Regulated Transcription Factors (e.g. Sp1, USF1)

* Diabetes-Inhibited

Figure 5. Mechanisms for glucose sensing in heart. Young et al., Circulation 105, 1861-70 (2002).

cellular reprogramming due to repetitive episodes of ischemia. The adaptation to reduced oxygen delivery results in the prevention of irreversible tissue damage. A functional characteristic of hibernating myocardium is improved contractile function with inotropic stimulation or reperfusion. A metabolic characteristic of hibernating myocardium is the switch from fat to glucose metabolism, accompanied by reactivation of the fetal gene program. Because glucose transport and phosphorylation is readily traced by the uptake and retention of [1BF] 2-deoxy, 2-fluoroglucose (FDG), hibernating myocardium is readily detected by enhanced glucose uptake and glycogen accumulation in the same regions.34,35 Like in fetal heart, the glycogen content of hibernating myocardium is dramatically increased. There is a direct correlation between glycogen content and myocardial levels of ATP,36 and one is tempted to speculate that improved "energetics" may be the result of improved glycogen metabolism in hibernating myocardium. The true mechanism for "viability remodeling" of ischemic myocardium is likely to be much more complex.

The vast literature on programmed cell death, or apoptosis,37,38 and our own observations on programmed cell survival36 support the idea of a direct link between metabolic pathways and the pathways of cell survival and destruction. Striking evidence for a link between cell survival and metabolism is found in cancer cells. Cancer cells not only possess an increased rate of glucose metabolism,39 they are also less likely to "commit suicide" when stressed.40 The same general principle appears to apply to the hibernating myocardium, where the downregulation of function and oxygen consumption is viewed as an adaptive response when coronary flow is impaired.41 In other words, metabolic reprogramming initiates and sustains the functional and structural feature of hibernating myocardium.

Recently, the hypothesis has been advanced that insulin promotes tolerance against ischemic cell death via the activation of innate cell-survival pathways in the heart.42 Specifically, activation of PI3 kinase, a downstream target of the insulin receptor substrate (IRS), and activation of protein kinase B/Akt, are mediators of antiapoptotic, cardioprotective signaling through activation of p70s6 kinase and inactivation of proapoptotic peptides. The major actor is Akt (pun not intended). Akt is located at the center of insulin and insulin-like growth factor 1 (IGF1) signaling. As the downstream serine-threonine kinase effector of PI3 kinase, Akt plays a key role in regulating cardiomyocyte growth and survival.43 Overexpression of constitutively active Akt raises myocardial glycogen levels and protects against ischemic damage in vivo and in vitro.44 Akt is also a modulator of metabolic substrate utilization.45 Phosphorylation of GLUT4 by Akt promotes its translocation and increases glucose uptake. Although the "insulin hypothesis" is attractive, there is good evidence showing that the signaling cascade is dependent on the first committed step of glycolysis and translocation of hexokinase to the outer mitochondrial membrane.46 47 These few examples illustrate the fact that signals detected by metabolic imaging of stressed or failing heart are the product of complex cellular reactions - truly only the tip of an iceberg.

Concluding remarks

Energy substrate metabolism and function of the heart are inextricably linked. For a given change in its environment the heart oxidizes the most efficient fuel. Substrate switching and metabolic flexibility are therefore features of normal cardiac function. Loss of metabolic flexibility and metabolic remodeling precede, trigger, and sustain functional and structural remodeling of the stressed heart. Here I highlight the pleio-tropic actions of metabolism in energy transfer, cardiac growth, gene expression, and viability. Examples are presented to illustrate that signals of stressed and failing heart are the product of complex cellular processes.

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