**8. Protein synthesis and sarcoplasmic protein expression in an ischemic cell**

Protein synthesis is a complex process that requires continuous and adequate energy intake, strict control of ionic homeostasis of the cell and the smooth functioning of many other pro‐ teins. Ischemia disrupts these necessary conditions and therefore profoundly affects protein synthesis beyond acute injury. However, the transcription of several genes is initiated at the onset of ischemia, and the mechanisms underlying this phenomenon are not fully under‐ stood. Nevertheless, it appears that the mass production of free radicals, the high concentra‐ tion of calcium, acidosis and the activation of the family of mitogen-activated protein kinases (MAP kinases) play an important role. Nuclear factor heat shock transcription fac‐ tor-1 (HSF-1) activates the expression of heat shock proteins (HSPs), a family of chaperone proteins, and inhibits the expression of other proteins. HSPs are synthesized in different sit‐ uations of stress, including hyperthermia, ischemia, hypoxia and mechanical stress, and are intended to prevent the structural modifications of key metabolic and cytoskeletal enzymes and inhibit the activity of caspases. [58]-[60]

The low oxygen partial pressure during ischemia activates other nuclear factors, such as hy‐ poxia-inducible factor-1alpha (HIF-1α). HIF-1α stimulates the transcription of many genes involved in cellular defense, such as those encoding NOS and GLUT-1, and other enzymes involved in glucose metabolism.[61]

In addition, ischemia activates innate immunity by stimulating sarcoplasmic receptors, such as the Toll-like receptors (TLR) TLR-2 and TLR-6, the synthesis and sarcoplasmic expression of which are increased. Receptor stimulation supports the synthesis of chemokines and cyto‐ kines and contributes to I/R injury.[61]-[66]

At the onset of ischemia, many substances are secreted by the cell. For example, ischemic cardiomyocytes secrete bradykinin, norepinephrine, angiotensin, adenosine, acetylcholine and opioids.[67]-[69] In addition, ischemia stimulates the expression of adhesion molecules, such as P-selectins, L-selectins, intercellular adhesion molecule-1 (ICAM-1) and platelet-en‐ dothelial cell adhesion molecules (PECAM), on the surface of endothelial cells, leukocytes and other ischemic cells. [62],[63],[70],[71] Furthermore, many cytokines, such as tumor ne‐ crosis factor-α, interleukin (IL)-1, IL-6 and IL-8, and vasoactive agents, such as endothelins and thromboxane A2, are secreted by cells in response to ischemia. [62],[70],[72] Cytokines and chemokines, the production of which dramatically increases during reperfusion, initiate the local inflammatory response and prepare for the recruitment of inflammatory cells into the injured area, respectively.

[8] Young LH, Renfu Y, Russell R, Hu X, Caplan M, Ren J, Shulman GI, Sinusas AJ: Lowflow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose

Impact of Ischemia on Cellular Metabolism http://dx.doi.org/10.5772/54509 13

[9] Stanley WC, Hall JL, Stone CK, Hacker TA: Acute myocardial ischemia causes a transmural gradient in glucose extraction but not glucose uptake. Am J Physiol 1992;

[10] Begum N, Graham AL, Sussman KE, Draznin B: Role of cAMP in mediating effects of fasting on dephosphorylation of insulin receptor. Am J Physiol 1992; 262: E142-9

[11] Dobson JG, Jr., Mayer SE: Mechanisms of activation of cardiac glycogen phosphory‐

[12] Morgan HE, Parmeggiani A: Regulation of Glycogenolysis in Muscle. Ii. Control of Glycogen Phosphorylase Reaction in Isolated Perfused Heart. J Biol Chem 1964; 239:

[13] Schaefer S, Ramasamy R: Glycogen utilization and ischemic injury in the isolated rat

[14] Schulze W, Krause EG, Wollenberger A: On the fate of glycogen phosphorylase in the ischemic and infarcting myocardium. J Mol Cell Cardiol 1971; 2: 241-51

[15] Kubler W, Spieckermann PG: Regulation of glycolysis in the ischemic and the anoxic

[16] Rovetto MJ, Whitmer JT, Neely JR: Comparison of the effects of anoxia and whole heart ischemia on carbohydrate utilization in isolated working rat hearts. Circ Res

[17] Wollenberger A, Krause EG: Metabolic control characteristics of the acutely ischemic

[18] Francis SH, Meriwether BP, Park JH: Interaction between adenine nucleotides and 3 phosphoglyceraldehyde dehydrogenase. II. A study of the mechanism of catalysis and metabolic control of the multi-functional enzyme. J Biol Chem 1971; 246: 5433-41

[19] Oguchi M, Meriwether BP, Park JH: Interaction between adenosine triphosphate and glyceraldehyde 3-phosphate dehydrogenase. 3. Mechanism of action and metabolic control of the enzyme under simulated in vivo conditions. J Biol Chem 1973; 248:

[20] Williamson JR: Glycolytic control mechanisms. II. Kinetics of intermediate changes during the aerobic-anoxic transition in perfused rat heart. J Biol Chem 1966; 241:

[21] Rovetto MJ, Lamberton WF, Neely JR: Mechanisms of glycolytic inhibition in ische‐

transporters to the sarcolemma in vivo. Circulation 1997; 95: 415-22

lase in ischemia and anoxia. Circ Res 1973; 33: 412-20

heart. Cardiovasc Res 1997; 35: 90-8

myocardium. J Mol Cell Cardiol 1970; 1: 351-77

myocardium. Am J Cardiol 1968; 22: 349-59

mic rat hearts. Circ Res 1975; 37: 742-51

262: H91-6

2435-9

1973; 32: 699-711

5562-70

5026-36
