InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Cardiology and Cardiovascular Medicine » "Artery Bypass", book edited by Wilbert S. Aronow, ISBN 978-953-51-1025-5, Published: March 13, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 1

Impact of Ischemia on Cellular Metabolism

By Maximilien Gourdin and Philippe Dubois
DOI: 10.5772/54509

Article top


Hydrolysis of Adenosine-triphosphate provides energy (30.5 kJ per mole) for biochemical reactions
Figure 1. Hydrolysis of Adenosine-triphosphate provides energy (30.5 kJ per mole) for biochemical reactions
This figure shows schematically oxidative metabolism, ATP production and the consequences of oxygen deprivation. GLUT-1 and GLUT-4: glucose transporters; GP: Glycogene phosphorylase; HK: Hexokinase; PF1K: Phosphofructo-1-kinase; GADPH: glyceraldehyde-3-phosphate dehydrogenase; NADH, H+: nicotinamide adenine dinucleotide; FADH2: flavine adenin dinucleotide; P: phosphate;AMP, adenosine monophosphate; adenosine diphosphate;ADP: adenosine diphosphate ATP: adenosine triphosphate; CO2 : carbon dioxide; O2 Oxygen; - : inhibition; + activation; H+: proton; e-: electron.
Figure 2. This figure shows schematically oxidative metabolism, ATP production and the consequences of oxygen deprivation. GLUT-1 and GLUT-4: glucose transporters; GP: Glycogene phosphorylase; HK: Hexokinase; PF1K: Phosphofructo-1-kinase; GADPH: glyceraldehyde-3-phosphate dehydrogenase; NADH, H+: nicotinamide adenine dinucleotide; FADH2: flavine adenin dinucleotide; P: phosphate;AMP, adenosine monophosphate; adenosine diphosphate;ADP: adenosine diphosphate ATP: adenosine triphosphate; CO2 : carbon dioxide; O2 Oxygen; - : inhibition; + activation; H+: proton; e-: electron.
This figure summarizes the ionic perturbations in an ischemic cell.
Figure 3. This figure summarizes the ionic perturbations in an ischemic cell.

Impact of Ischemia on Cellular Metabolism

Maximilien Gourdin1 and Philippe Dubois1

1. Introduction

As in all aerobic eukaryotic cells, oxygen is essential for homeostasis in human cells. The interruption of blood flow to tissues results in an arrested oxygen supply and disrupts the biochemical reactions that ensure the smooth functioning, integrity and survival of the cells. The limited oxygen reserves that are dissolved in the interstitial fluid and are bound to hemoglobin, myoglobin and neuroglobin do not maintain efficient, long-term metabolism.[1,2] Lack of oxygen affects all functions within the cell. Table 1 summarizes the main cellular consequences of ischemia.

(1) cellular acidosis;
(2) loss of sarcoplasmic membrane potential;
(3) cellular swelling;
(4) cytoskeleton disorganization;
(5) reduction of adenosine-5’-triphospate (ATP) and phosphocreatine is more than reduction in the energy substrates;
(6) reduction of glutathione, of a-tocopherol;
(7) increasing expression of leukocyte adhesion molecules;
(8) secretion of cytokines/chemokines
- Tumor Necrosis Factor (TNF-α)
- Interleukins (IL-) -1, 6, 8

Table 1.

Major cellular consequences of ischemia

2. Adenosine triphosphate depletion

Eukaryotic cells contain mitochondria, organelles whose main function is to produce adenosine triphosphate (ATP). ATP is an essential energy substrate, as its hydrolysis provides energy for many metabolic and biochemical reactions involved in development, adaptation and cell survival. ATP production in an aerobic cell is particularly effective when the degradation of key nutrients such as glucose and fatty acids is coupled to a supramolecular complex located in the inner membrane of mitochondria to drive oxidative phosphorylation. Oxidative phosphorylation is mediated by an electron transport chain that consists of four protein complexes and establishes a transmembrane electrochemical gradient by supporting the accumulation of protons in the intermembrane space of the mitochondria. This gradient is used as an energy source by ATP synthase during the synthesis of an ATP molecule from a molecule of adenosine diphosphate (ADP) and an inorganic phosphate (Figure 1). Without oxygen, oxidative phosphorylation stops: the proton gradient between the intermembrane space and the inner mitochondria is abolished, and ATP synthesis is interrupted. The ensuing rapid fall in intracellular ATP induces a cascade of events leading to reversible cell damage. However, over time, the damage increases and gradually becomes irreversible, which may lead to cell death and destruction of the parenchymal tissue.


Figure 1.

Hydrolysis of Adenosine-triphosphate provides energy (30.5 kJ per mole) for biochemical reactions

When devoid of ATP, the cell derives its energy from the pyrophosphate bonds of ADP as they are degraded to adenosine monophosphate (AMP) and then to adenosine. Adenosine diffuses freely out of the cell, dramatically reducing the intracellular pool of adenine nucleotides, the precursors for ATP.

3. Changes in metabolism (Figure 2)

In the presence of oxygen, human cells respire and derive their energy from the complete degradation of food (fats, carbohydrates and amino acids) by specific oxidative processes that fuel oxidative phosphorylation. A lack of oxygen completely changes these metabolic pathways, disrupting glycolysis and inhibiting the degradation pathways of lipids (beta-oxidation), amino acids and oxidative phosphorylation.

3.1. Glucose metabolism

During ischemia, the cell will change not only its glucose supply routes but also its glycolysis pathways and transition from aerobic glycolysis to anaerobic glycolysis. When this happens, the available cytosolic glucose is metabolized by anaerobic glycolysis and becomes the main source of ATP. The efficiency of this process is much lower than that of aerobic glycolysis coupled to oxidative phosphorylation; the anaerobic degradation of one molecule of glucose produces 2 ATP molecules compared to the 36 ATP molecules that are produced under aerobic conditions. Consumption quickly exceeds production, and the intracellular concentration of ATP decreases. For example, in the heart, the degree of glycolysis inhibition is directly proportional to the severity of coronary flow restriction.[3]-[5]

3.1.1. Glucose supply

With the complete interruption of or decrease in blood flow, the extracellular concentration of glucose drops very quickly. First, the cell optimizes the uptake of glucose from the interstitial space by improving glucose transmembrane transport by increasing the sarcoplasmic expression of the high-affinity glucose transporters GLUT-1 and GLUT-4. [6]-[8] This protective mechanism temporarily compensates for the decrease in extracellular glucose concentration. Next, the cell uses its intracellular glucose stores of glycogen. [9] The decrease in intracellular ATP and glucose-6-phosphate, the rising lactate/pyruvate ratio and the increase in intracellular AMP and the inorganic phosphate concentration activate a phosphorylase kinase, which catalyses the conversion of glycogene phosphorylase b to its active form, glycogene phosphorylase a. This cascade reaction leads to an intense and rapid consumption of glycogen. [10]-[14]

3.1.2. Glycolysis pathways

The inhibition of oxidative phosphorylation caused by lack of oxygen does not allow the pyruvate produced by glycolysis to be degraded. Under aerobic conditions, pyruvate is transported into the mitochondria and feeds into the Krebs cycle, which provides the nicotinamide adenine dinucleotide (NADH, H+) and flavine adenine dinucleotide (FADH2) cofactors for oxidative phosphorylation, significantly increasing the yield of glycolysis.

Ischemia modulates the activity of the following two key enzymes of anaerobic glycolysis: phosphofructo-1-kinase (PF1K) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Following the onset of ischemia, or during moderate ischemia, the activation of glycogenolysis accelerates glycolysis.[15]-[17] The decrease in both intracellular ATP and creatine phosphate, along with increases in the intracellular concentrations of AMP, inorganic phosphate and fructose-1,6-bisphosphate, intensify the activity of PF1K and GAPDH. [17]-[20]

During prolonged or sustained ischemia, the low intracellular glucose concentration, the disappearance of glycogen and severe intracellular acidosis eventually inhibit PF1K. Furthermore, high concentrations of lactate and protons in ischemic tissues also inhibit GAPDH. [21],[22]

Moreover, the lactate/pyruvate ratio, intracellular acidosis and the absence of regenerated essential cofactors, such as NADH,H+, affect the catalytic activity of the other enzymes involved in the initial step of glycolysis and prevent the optimal performance of anaerobic glycolysis. [23]

3.2. Lipid metabolism (Figure 2)

The importance of oxygen in functional oxidative phosphorylation leads to a significant reduction in ATP production from the beta-oxidation of fatty acids that is proportional to the degree of ischemia. In mild to moderate ischemia, the rate of fatty acid oxidation decreases but still fuels oxidative phosphorylation. [4],[24] In more severe ischemia, the lack of the cofactors NADH,H+ and FAD+, which are normally regenerated through oxidative phosphorylation, completely inhibits acyl-CoenzymeA (acyl-CoA) dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase, which are key beta-oxidation enzymes.[4],[25] The cytosolic concentrations of fatty acids, acyl-CoA and acylcarnitine rise gradually. [26]-[28] The accumulation of these amphiphilic compounds in ischemic tissues has major functional implications. They dissolve readily in cell membranes and affect the functional properties of membrane proteins. Decreased activity of Na+/K+-ATPase and the sarcoplasmic and endoplasmic reticulum Ca2+-ATPase pumps, as well as the activation of ATP-dependent potassium channels, reduces the inwardly rectifying potassium current and prolongs the opening of Na+ channels, delaying their inactivation.[29]-[31] The accumulation of amphiphilic compounds produces a time-dependent reversible reduction in gap-junction conductance. [31]

3.3. Metabolite detoxification pathways

Reducing the intracellular concentration of ATP inhibits the hexose phosphate cycle. This metabolic pathway regenerates glutathione, ascorbic acid and tocopherol, which are involved in the detoxification of metabolites from the cytosol and the sarcoplasmic membrane.

4. Intracellular acidosis

Intracellular acidosis is a cardinal feature of cellular ischemia. The increased production of protons due to metabolic modifications very quickly saturates the buffering capacity of the cell. Intracellular acidosis interferes directly and indirectly with the optimal functioning of the cell by increasing intracellular Na+ through the activation of Na+/H+ exchangers and by Ca2+ activation of Na+/Ca2+ exchangers, increasing the production of free radicals; changing the affinity of different proteins, such as enzymes and troponin C, to Ca2+; modifying tertiary protein structures; inhibiting enzymes; and disrupting the function of sarcoplasmic pumps and carriers.[29]


Figure 2.

This figure shows schematically oxidative metabolism, ATP production and the consequences of oxygen deprivation. GLUT-1 and GLUT-4: glucose transporters; GP: Glycogene phosphorylase; HK: Hexokinase; PF1K: Phosphofructo-1-kinase; GADPH: glyceraldehyde-3-phosphate dehydrogenase; NADH, H+: nicotinamide adenine dinucleotide; FADH2: flavine adenin dinucleotide; P: phosphate;AMP, adenosine monophosphate; adenosine diphosphate;ADP: adenosine diphosphate ATP: adenosine triphosphate; CO2 : carbon dioxide; O2 Oxygen; - : inhibition; + activation; H+: proton; e-: electron.

The main source of protons during ischemia comes from the production of lactate from pyruvate by lactate dehydrogenase. The accumulation of extracellular lactate greatly reduces the effectiveness of the lactate/proton cotransporter, preventing the removal of protons. Additionally, the residual metabolic activity also contributes to acidosis, as the hydrolysis of an ATP molecule releases a proton.

5. Changes in the ionic cellular equilibrium (Figure 3)

Ischemia induces a profound disturbance of the ionic homeostasis of a cell. The two major changes are the loss of ionic transmembrane gradients, which causes membrane depolarization, and increased intracellular sodium ([Na+]i), which is responsible for inducing a rise in the intracellular calcium ([Ca2+]i) levels, leading to cellular edema.

Cellular depolarization occurs very rapidly after the onset of ischemia, and these mechanisms are not fully understood. However, it is recognized that both the inhibition of the Na+/K+-ATPase and the opening of ATP-dependent K+ channels play a crucial role. Cellular depolarization is characterized by a negative outgoing current and a decrease in the extracellular concentrations of Na+, Cl- and Ca2+, as well as an increase in the extracellular concentration of K+. Progressive depolarization of the cell also promotes prolonged activation of voltage-dependent sodium channels. [29]

The accumulation of sodium in the cytosol is multifactorial. Acidosis stimulates Na+/H+ exchangers to purge cellular H+, which results in increased intracellular Na+.[32]-[34] This net movement of Na+ is accompanied by osmotic water movement. Moreover, inhibition of the Na+/K+-ATPase due to a lack of ATP prevents the removal of excess intracellular Na+. The high intracellular concentration of Na+ affects the function of other membrane transporters, such as the Na+/Ca2+ antiporter, an accelerator. This allows the extrusion of sodium from the cell at the expense of an intracellular accumulation of Ca2+. The massive entry of calcium into the cell disrupts the mechanisms that regulate its intracellular concentration and induces the release of calcium from the intracellular endoplasmic reticulum stores.[35] The lack of ATP prevents calcium excretion into the interstitium and its sequestration in the endoplasmic reticulum. The accumulation of cytosolic calcium induces degradation of membrane phospholipids and cytoskeletal proteins, alters the both the calcium affinity and the efficiency of proteins involved in contractility, activates nitric oxide synthase (NOS) and proteases such as calpains and caspases, promotes the production of free radicals and alters the tertiary structure of enzymes such as xanthine dehydrogenase, which is converted to xanthine oxidase. [36]-[38]

6. Mitochondria

The mitochondrion plays a central role in ischemic injury. Not only is it the site of critical biochemical reactions in the cell, such as oxidative phosphorylation, beta-oxidation and the citric acid cycle, but it also occupies a unique position in the cellular balance between life and death. Inhibition of the mitochondrial respiratory chain as a result of oxygen deprivation is the cornerstone of metabolic disturbances.


Figure 3.

This figure summarizes the ionic perturbations in an ischemic cell.

6.1. Disturbance of ATP synthesis.

Without the respiratory chain oxidation-reduction reactions, proton accumulation in the mitochondrial intermembrane space is interrupted, disrupting the electrochemical gradient that allows ATP synthase to synthesize ATP. During ischemia, the proton-translocating F0F1-ATP synthase, which normally produces ATP, becomes an F0F1-ATPase and consumes ATP in order to pump protons from the matrix to the intermembrane space and maintain the mitochondrial membrane potential.[39],[40] The mitochondria therefore become a site of ATP consumption produced by anaerobic glycolysis.

6.2. An increase in free radical production

Free radical oxygen species (ROS) are highly reactive chemical compounds because they have unpaired electrons in their electron cloud. ROS are capable of oxidizing cellular constituents such as proteins, deoxyribonucleic acid (DNA), membrane phospholipids and other adjacent biological structures. In addition to their role in ischemia, ROS are constitutively generated during metabolic processes and have an important role in cell signaling. Mitochondrial respiration constitutively produces a small amount of ROS, primarily the superoxide anion O2-● at complexes I and III of the electron transport chain. The anion is rapidly converted to hydrogen peroxide (H2O2) by metallo-enzymes and superoxide dismutase (SOD). [41]-[43] Cellular stress, particularly oxidative stress, dramatically increases mitochondrial ROS production by disrupting and later inhibiting oxidative phosphorylation. Moreover, the rise in mitochondrial calcium increases ROS production and greatly decreases the antioxidant capacity of mitochondria by decreasing the glutathione peroxidase concentration and SOD activity.

6.3. Intramitochondrial calcium overload

The mitochondrial calcium concentration is in equilibrium between its cytosolic concentration and the proton gradient on either side of the inner membrane of mitochondria. The loss of this gradient due to the inhibition of the respiratory chain, as well as the elevated cytosolic calcium that results from ischemia, allows for the accumulation of calcium in the mitochondria and promotes mitochondrial swelling and the opening of the permeability transition pore.

6.4. Opening of the mitochondrial permeability transition pore

Ischemic disturbances within mitochondria, such as calcium overload, loss of membrane potential, oxidative stress, mass production of free radicals, low NADPH/NADP+ and reduced glutathione to oxidized glutathione ratios (GSH/GSSG), low intra-mitochondrial concentration of ATP or high inorganic phosphate, will promote opening of the permeability transition pore (mPTP) upon reperfusion, a major player in I/R injury-mediated cell lethality.[42],[44] mPTP is a nonspecific channel, and its opening suddenly increases the permeability of the inner mitochondrial membrane to both water and various molecules of high molecular weight (> 1,500 kDa). The opening of mPTPs abolishes the mitochondrial membrane potential and uncouples oxidative phosphorylation, which empties the mitochondria of its matrix and induces apoptosis by releasing the intra-mitochondrial proteins cytochrome c, endonuclease G, Smac/Diablo and apoptosis-inducing factor into the cytosol. [44]-[52]

7. Structural and functional modifications

The cytoskeleton, the internal structural organization of a cell, is composed of a highly regulated complex network of organized structural proteins, including actin, microtubules and lamins. The cytoskeleton performs multiple functions. It maintains internal cellular compartmentalization and mediates the transmission of mechanical forces within the cell to adjacent cells and the extracellular matrix, the distribution of organelles, the movement of molecules or components and the docking of proteins such as membrane receptors or ion channels. Ischemia deconstructs the cytoskeleton. [53]-[56] The high intracellular concentrations of Ca2+ that are associated with ischemia activate multiple phosphorylases and proteases that disassemble and degrade the cytoskeleton, thereby eliminating the functions that rely on its integrity, such as phagocytosis, exocytosis, myofilament contraction, intercellular communication and cell anchorage. Destruction of the internal architecture worsens I/R injuries and leads to apoptosis. [53],[56],[57] During ischemia, all elements of the cytoskeleton are affected, but with different kinetics.[54],[55] Moreover, the accumulation of osmotically active particles, including lactate, sodium, inorganic phosphate and creatine, induces cellular oedema.[38]

Regulatory cellular mechanisms provide intracellular homeostasis that enables optimal enzyme function in a relatively narrow range of environmental conditions. The conditions created by ischemia, such as acidosis and calcium overload, modify or inhibit the activity of many enzymes due to changes in the pH and tertiary structures, affecting cellular metabolism. For example, ischemia induces the conversion of xanthine dehydrogenase to xanthine oxidase.[36]-[38] These two enzymes catalyze the same reactions, converting hypoxanthine to xanthine and xanthine to uric acid. The first reaction uses NAD+ as a cofactor, whereas the second uses oxygen and produces O2-●, a free radical.

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 proteins. 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 understood. Nevertheless, it appears that the mass production of free radicals, the high concentration 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 factor-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 situations 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 hypoxia-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 cytokines 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-endothelial 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 necrosis 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.


1 - Jennings RB, Murry CE, Steenbergen C, Jr., Reimer KA: Development of cell injury in sustained acute ischemia. Circulation 1990; 82: II2-12
2 - Kloner RA, Jennings RB: Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation 2001; 104: 2981-9
3 - Neely JR, Liedtke AJ, Whitmer JT, Rovetto MJ: Relationship between coronary flow and adenosine triphosphate production from glycolysis and oxidative metabolism. Recent Adv Stud Cardiac Struct Metab 1975; 8: 301-21
4 - Neely JR, Morgan HE: Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 1974; 36: 413-59
5 - Neely JR, Whitmer JT, Rovetto MJ: Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts. Circ Res 1975; 37: 733-41
6 - Sun D, Nguyen N, DeGrado TR, Schwaiger M, Brosius FC, 3rd: Ischemia induces translocation of the insulin-responsive glucose transporter GLUT4 to the plasma membrane of cardiac myocytes. Circulation 1994; 89: 793-8
7 - Tian R, Abel ED: Responses of GLUT4-Deficient Hearts to Ischemia Underscore the Importance of Glycolysis. Circulation 2001; 103: 2961-2966
8 - Young LH, Renfu Y, Russell R, Hu X, Caplan M, Ren J, Shulman GI, Sinusas AJ: Low-flow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo. Circulation 1997; 95: 415-22
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; 262: H91-6
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 phosphorylase in ischemia and anoxia. Circ Res 1973; 33: 412-20
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: 2435-9
13 - Schaefer S, Ramasamy R: Glycogen utilization and ischemic injury in the isolated rat heart. Cardiovasc Res 1997; 35: 90-8
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 myocardium. J Mol Cell Cardiol 1970; 1: 351-77
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 1973; 32: 699-711
17 - Wollenberger A, Krause EG: Metabolic control characteristics of the acutely ischemic myocardium. Am J Cardiol 1968; 22: 349-59
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: 5562-70
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: 5026-36
21 - Rovetto MJ, Lamberton WF, Neely JR: Mechanisms of glycolytic inhibition in ischemic rat hearts. Circ Res 1975; 37: 742-51
22 - Williamson JR: Effects of insulin and diet on the metabolism of L-lactate and glucose by the perfused rat heart. Biochem J 1962; 83: 377-83
23 - Fleet WF, Johnson TA, Graebner CA, Gettes LS: Effect of serial brief ischemic episodes on extracellular K+, pH, and activation in the pig. Circulation 1985; 72: 922-32
24 - Calvani M, Reda E, Arrigoni-Martelli E: Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions. Basic Res Cardiol 2000; 95: 75-83
25 - Neely JR, Feuvray D: Metabolic products and myocardial ischemia. Am J Pathol 1981; 102: 282-91
26 - Ford DA, Gross RW: Differential accumulation of diacyl and plasmalogenic diglycerides during myocardial ischemia. Circ Res 1989; 64: 173-7
27 - Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD: Targeting fatty acid and carbohydrate oxidation--a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta; 1813: 1333-50
28 - van der Vusse GJ, Glatz JF, Stam HC, Reneman RS: Fatty acid homeostasis in the normoxic and ischemic heart. Physiol Rev 1992; 72: 881-940
29 - Martin C, Riou B, Vallet B: Physiologie humaine appliquée. 2006: First Edition, Chapter 17, pp 217-227
30 - McHowat J, Yamada KA, Wu J, Yan GX, Corr PB: Recent insights pertaining to sarcolemmal phospholipid alterations underlying arrhythmogenesis in the ischemic heart. J Cardiovasc Electrophysiol 1993; 4: 288-310
31 - Yamada KA, McHowat J, Yan GX, Donahue K, Peirick J, Kleber AG, Corr PB: Cellular uncoupling induced by accumulation of long-chain acylcarnitine during ischemia. Circ Res 1994; 74: 83-95
32 - Lazdunski M, Frelin C, Vigne P: The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol 1985; 17: 1029-42
33 - Nawada R, Murakami T, Iwase T, Nagai K, Morita Y, Kouchi I, Akao M, Sasayama S: Inhibition of sarcolemmal Na+,K+-ATPase activity reduces the infarct size-limiting effect of preconditioning in rabbit hearts. Circulation 1997; 96: 599-604
34 - Tani M, Neely JR: Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+-Na+ and Na+-Ca2+ exchange. Circ Res 1989; 65: 1045-56
35 - Silver IA, Erecinska M: Ion homeostasis in rat brain in vivo: intra- and extracellular [Ca2+] and [H+] in the hippocampus during recovery from short-term, transient ischemia. J Cereb Blood Flow Metab 1992; 12: 759-72
36 - Chambers DE, Parks DA, Patterson G, Roy R, McCord JM, Yoshida S, Parmley LF, Downey JM: Xanthine oxidase as a source of free radical damage in myocardial ischemia. J Mol Cell Cardiol 1985; 17: 145-52
37 - Granger DN: Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol 1988; 255: H1269-75
38 - Maxwell SR, Lip GY: Reperfusion injury: a review of the pathophysiology, clinical manifestations and therapeutic options. Int J Cardiol 1997; 58: 95-117
39 - Grover GJ, Atwal KS, Sleph PG, Wang FL, Monshizadegan H, Monticello T, Green DW: Excessive ATP hydrolysis in ischemic myocardium by mitochondrial F1F0-ATPase: effect of selective pharmacological inhibition of mitochondrial ATPase hydrolase activity. Am J Physiol Heart Circ Physiol 2004; 287: H1747-55
40 - Murphy E, Steenbergen C: Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 2008; 88: 581-609
41 - Balaban RS, Nemoto S, Finkel T: Mitochondria, oxidants, and aging. Cell 2005; 120: 483-95
42 - Di Lisa F, Canton M, Menabo R, Kaludercic N, Bernardi P: Mitochondria and cardioprotection. Heart Fail Rev 2007; 12: 249-60
43 - Turrens JF: Mitochondrial formation of reactive oxygen species. J Physiol 2003; 552: 335-44
44 - Hausenloy DJ, Yellon DM: Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther 2007; 116: 173-91
45 - Akao M, O'Rourke B, Teshima Y, Seharaseyon J, Marban E: Mechanistically distinct steps in the mitochondrial death pathway triggered by oxidative stress in cardiac myocytes. Circ Res 2003; 92: 186-94
46 - Costantini P, Chernyak BV, Petronilli V, Bernardi P: Selective inhibition of the mitochondrial permeability transition pore at the oxidation-reduction sensitive dithiol by monobromobimane. FEBS Lett 1995; 362: 239-42
47 - Costantini P, Chernyak BV, Petronilli V, Bernardi P: Modulation of the mitochondrial permeability transition pore by pyridine nucleotides and dithiol oxidation at two separate sites. J Biol Chem 1996; 271: 6746-51
48 - Crompton M: The mitochondrial permeability transition pore and its role in cell death. Biochem J 1999; 341 (Pt 2): 233-49
49 - Danial NN, Korsmeyer SJ: Cell death: critical control points. Cell 2004; 116: 205-19
50 - Gustafsson AB, Gottlieb RA: Bcl-2 family members and apoptosis, taken to heart. Am J Physiol Cell Physiol 2007; 292: C45-51
51 - Javadov S, Karmazyn M: Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection. Cell Physiol Biochem 2007; 20: 1-22
52 - Kroemer G, Galluzzi L, Brenner C: Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007; 87: 99-163
53 - Cao HM, Wang Q, You HY, Li J, Yang ZY: Stabilizing microtubules decreases myocardial ischaemia-reperfusion injury. J Int Med Res 2011 39: 1713-9
54 - Hein S, Scheffold T, Schaper J: Ischemia induces early changes to cytoskeletal and contractile proteins in diseased human myocardium. J Thorac Cardiovasc Surg 1995; 110: 89-98
55 - Iwai K, Hori M, Kitabatake A, Kurihara H, Uchida K, Inoue M, Kamada T: Disruption of microtubules as an early sign of irreversible ischemic injury. Immunohistochemical study of in situ canine hearts. Circ Res 1990; 67: 694-706
56 - Nakamura Y, Miura T, Nakano A, Ichikawa Y, Yano T, Kobayashi H, Ikeda Y, Miki T, Shimamoto K: Role of microtubules in ischemic preconditioning against myocardial infarction. Cardiovasc Res 2004; 64: 322-30
57 - Ganote C, Armstrong S: Ischaemia and the myocyte cytoskeleton: review and speculation. Cardiovasc Res 1993; 27: 1387-403
58 - Chi NC, Karliner JS: Molecular determinants of responses to myocardial ischemia/reperfusion injury: focus on hypoxia-inducible and heat shock factors. Cardiovasc Res 2004; 61: 437-47
59 - Stetler RA, Gao Y, Zhang L, Weng Z, Zhang F, Hu X, Wang S, Vosler P, Cao G, Sun D, Graham SH, Chen J: Phosphorylation of HSP27 by Protein Kinase D Is Essential for Mediating Neuroprotection against Ischemic Neuronal Injury. J Neurosci 2012; 32: 2667-82
60 - Williams RS, Benjamin IJ: Protective responses in the ischemic myocardium. J Clin Invest 2000; 106: 813-8
61 - Michiels C, Minet E, Michel G, Mottet D, Piret JP, Raes M: HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases. IUBMB Life 2001; 52: 49-53
62 - Eltzschig HK, Collard CD: Vascular ischaemia and reperfusion injury. Br Med Bull 2004; 70: 71-86
63 - Eltzschig HK, Eckle T: Ischemia and reperfusion--from mechanism to translation. Nat Med 2011 1391-401
64 - Into T, Kanno Y, Dohkan J, Nakashima M, Inomata M, Shibata K, Lowenstein CJ, Matsushita K: Pathogen recognition by Toll-like receptor 2 activates Weibel-Palade body exocytosis in human aortic endothelial cells. J Biol Chem 2007; 282: 8134-41
65 - Kuhlicke J, Frick JS, Morote-Garcia JC, Rosenberger P, Eltzschig HK: Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS One 2007; 2: e1364
66 - Kuo MC, Patschan D, Patschan S, Cohen-Gould L, Park HC, Ni J, Addabbo F, Goligorsky MS: Ischemia-induced exocytosis of Weibel-Palade bodies mobilizes stem cells. J Am Soc Nephrol 2008; 19: 2321-30
67 - Arai M, Tejima K, Ikeda H, Tomiya T, Yanase M, Inoue Y, Nagashima K, Nishikawa T, Watanabe N, Omata M, Fujiwara K: Ischemic preconditioning in liver pathophysiology. J Gastroenterol Hepatol 2007; 22 Suppl 1: S65-7
68 - Kato R, Foex P: Myocardial protection by anesthetic agents against ischemia-reperfusion injury: an update for anesthesiologists. Can J Anaesth 2002; 49: 777-91
69 - Martorana PA, Kettenbach B, Breipohl G, Linz W, Scholkens BA: Reduction of infarct size by local angiotensin-converting enzyme inhibition is abolished by a bradykinin antagonist. Eur J Pharmacol 1990; 182: 395-6
70 - Briaud SA, Ding ZM, Michael LH, Entman ML, Daniel S, Ballantyne CM: Leukocyte trafficking and myocardial reperfusion injury in ICAM-1/P-selectin-knockout mice. Am J Physiol Heart Circ Physiol 2001; 280: H60-7
71 - Yadav SS, Howell DN, Gao W, Steeber DA, Harland RC, Clavien PA: L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver. Am J Physiol 1998; 275: G1341-52
72 - Kakkar AK, Lefer DJ: Leukocyte and endothelial adhesion molecule studies in knockout mice. Curr Opin Pharmacol 2004; 4: 154-8