Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian heart is normally well oxygenated and anaerobic glycolysis is extremely rare except for the production of extra ATP during extreme exercise like a marathon race. Anaerobic glycolysis plays a role when there is a serious impairment in coronary blood flow such as during heart attack and open heart surgery. The control of glycolysis in ischemic myocardial tissue appears to be extremely complex. During aerobic glycolysis, phosphofructokinase is the most important regulatory enzyme that controls the energy requirements of the cell. Under anaerobic conditions, however, glyceraldehyde-3-phosphate dehydrogenase becomes the key enzyme because it responds promptly to any changes in the essential supply of co-factors for oxidation. The conversion of pyruvate to acetyl CoA (aerobic metabolism) involves a series of chain reactions primarily catalyzed by pyruvate dehydrogenase complex which is situated at the cross roads between both aerobic and anaerobic glycolysis. It is important to remember that substrate utilization is carefully controlled by substrate availability. During aerobic metabolism, control mechanisms using fatty acids, lactate and glucose as energy substrates regulate the rate of ATP production according to energy demand. This precise mechanism is upset during ischemia and post-ischemic reperfusion for reasons discussed in this review. The demand for ATP can no longer be met by its supply because of severely reduced anaerobic glycolysis and significantly inhibited beta-oxidation of fatty acids. The impairment of bioenergetics is discussed in the context of several diseases such as cardiomyopathy, heart failure, diabetes, arrhythmias, cardiac surgery, heart-lung transplantation, and also in aging and oxidative stress. The regulation of energy metabolism in preconditioned heart is also discussed. Finally, methods used to preserve energy in ischemic myocardium are summarized and quantitation of the high-energy phosphates is discussed. This review challenges scientists to discover drugs which will stimulate energy supply during myocardial ischemia.
 ...
PMID:Bioenergetics, ischemic contracture and reperfusion injury. 880 94

Skeletal muscle contraction during ischemia, such as that experienced by peripheral vascular disease patients, is characterized by rapid fatigue. Using a canine gracilis model, we tested the hypothesis that a critical factor determining force production during ischemia is the metabolic response during the transition from rest to steady state. Dichloroacetate (DCA) administration before gracilis muscle contraction increased pyruvate dehydrogenase complex activation and resulted in acetylation of 80% of the free carnitine pool to acetylcarnitine. After 1 min of contraction, phosphocreatine (PCr) degradation in the DCA group was approximately 50% lower than in the control group (P < 0.05) during conditions of identical force production. After 6 min of contraction, steady-state force production was approximately 30% higher in the DCA group (P < 0.05), and muscle ATP, PCr, and glycogen degradation and lactate accumulation were lower (P < 0.05 in all cases). It appears, therefore, that an important determinant of contractile function during ischemia is the mechanisms by which ATP regeneration occurs during the period of rest to steady-state transition.
 ...
PMID:Metabolic responses from rest to steady state determine contractile function in ischemic skeletal muscle. 927 74

Previous studies have identified changes in the activities of the pyruvate dehydrogenase complex (PDHC) and cytochrome c oxidase during early recirculation following short-term cerebral ischemia. However, the relationship of these changes to the delayed selective neuronal loss that develops as a result of short-term ischemia is incompletely defined. The effects of ischemia and recirculation on the activities of these enzymes in the dorsolateral striatum, a region containing many susceptible neurons, and the ischemia-resistant paramedian cortex have been compared. No significant loss of activity of cytochrome c oxidase was seen in either region during the first few hours of recirculation following 30 min of ischemia. A decrease (of 32%) was observed at 24 h in the dorsolateral striatum. However, this probably resulted from changes in the mitochondrial fraction due to advanced neuronal degeneration. By contrast, there was a significant decrease (by 24%) in activity of PDHC at 3 h following a 30-min, but not a 10-min, ischemic period. Only the 30-min ischemic period resulted in extensive delayed neuronal loss. In the paramedian cortex, there was no significant change in PDHC and no neuronal loss following either ischemic period. These results provide strong evidence for a close association between neuronal loss and changes in the activity of PDHC but not cytochrome c oxidase in the dorsolateral striatum.
 ...
PMID:Reduced activity of the pyruvate dehydrogenase complex but not cytochrome c oxidase is associated with neuronal loss in the striatum following short-term forebrain ischemia. 940 51

We have demonstrated previously that dichloroacetate can attenuate skeletal muscle fatigue by up to 35% in a canine model of peripheral ischemia (Timmons, J.A., S.M. Poucher, D. Constantin-Teodosiu, V. Worrall, I.A. Macdonald, and P.L. Greenhaff. 1996. J. Clin. Invest. 97:879-883). This was thought to be a consequence of dichloroacetate increasing acetyl group availability early during contraction. In this study we characterized the metabolic effects of dichloroacetate in a human model of peripheral muscle ischemia. On two separate occasions (control-saline or dichloroacetate infusion), nine subjects performed 8 min of single-leg knee extension exercise at an intensity aimed at achieving volitional exhaustion in approximately 8 min. During exercise each subject's lower limbs were exposed to 50 mmHg of positive pressure, which reduces blood flow by approximately 20%. Dichloroacetate increased resting muscle pyruvate dehydrogenase complex activation status by threefold and elevated acetylcarnitine concentration by fivefold. After 3 min of exercise, phosphocreatine degradation and lactate accumulation were both reduced by approximately 50% after dichloroacetate pretreatment, when compared with control conditions. However, after 8 min of exercise no differences existed between treatments. Therefore, it would appear that dichloroacetate can delay the accumulation of metabolites which lead to the development of skeletal muscle fatigue during ischemia but does not alter the metabolic profile when a maximal effort is approached.
 ...
PMID:Substrate availability limits human skeletal muscle oxidative ATP regeneration at the onset of ischemic exercise. 942 69

The mechanisms of selective neuronal loss after short-term global ischemia remain undefined, but processes including increased proteolytic activity, impaired protein synthesis, and oxidative damage have been proposed to contribute. A decrease in activity of the pyruvate dehydrogenase complex in the dorsolateral striatum, an ischemia-susceptible region, is one change apparently differentiating this region from ischemia-resistant areas during early recirculation. To provide an insight into processes contributing to postischemic cell damage, the changes in the pyruvate dehydrogenase complex during early recirculation have been further characterized. These studies provide clear confirmation that the activity of the pyruvate dehydrogenase complex is reduced in mitochondria from the dorsolateral striatum by 3 h of recirculation. The decrease in activity was not accompanied by a loss of antigenic sites or by changes in electrophoretic mobility of the components of the complex. A reduction in activity of the E1 component of the complex (39-42% decrease), but not the E2 and E3 components, was observed that was apparently sufficient to explain the decrease in activity of the whole complex. These results indicate that the changes in activity of the pyruvate dehydrogenase complex in the dorsolateral striatum are not due to loss or gross disruption of the constituent proteins but rather most likely reflect a selective inactivation of a specific component of the complex.
 ...
PMID:The pyruvate dehydrogenase complex is partially inactivated during early recirculation following short-term forebrain ischemia in rats. 942 67

Chronic impairment of aerobic energy metabolism accompanies global cerebral ischemia and reperfusion and likely contributes to delayed neuronal cell death. Reperfusion-dependent inhibition of pyruvate dehydrogenase complex (PDHC) enzyme activity has been described and proposed to be at least partially responsible for this metabolic abnormality. This study tested the hypothesis that global cerebral ischemia and reperfusion results in the loss of pyruvate dehydrogenase immunoreactivity and that such loss is associated with selective neuronal vulnerability to transient ischemia. Following 10 min canine cardiac arrest, resuscitation, and 2 or 24 h of restoration of spontaneous circulation, brains were either perfusion fixed for immunohistochemical analyses or biopsy samples were removed for Western immunoblot analyses of PDHC immunoreactivity. A significant decrease in immunoreactivity was observed in frontal cortex homogenates from both 2 and 24 h reperfused animals compared to samples from nonischemic control animals. These results were supported by confocal microscopic immunohistochemical determinations of pyruvate dehydrogenase immunoreactivity in the neuronal cell bodies located within different layers of the frontal cortex. Loss of immunoreactivity was greatest for pyramidal neurons located in layer V compared to neurons in layers IIIc/IV, which correlates with a greater vulnerability of layer V neurons to delayed death caused by transient global cerebral ischemia.
 ...
PMID:Neuronal subclass-selective loss of pyruvate dehydrogenase immunoreactivity following canine cardiac arrest and resuscitation. 1068 78

This in vitro study was designed to examine the efficacy of exogenous pyruvate and glucose as a fuel substrate to protect rat astrocytes from post-ischemic injury. Astrocytes were incubated in Kreb's buffer deprived of oxygen and glucose for 6 h (ischemia) followed by incubation with added pyruvate or glucose and normoxia for the next 6 h (reperfusion). The transformation of reactive astrocytes in response to various treatments was examined by immunostaining with glial fibrillary acidic protein. The extent of cell damage was evaluated in terms of lactate dehydrogenase leakage from the cells and altered intracellular redox status. The mechanism of cell death was determined by immunoblotting with cytochrome C, caspase-3 and PARP antibodies. The mechanism of the action of pyruvate was determined by measuring the activity of pyruvate dehydrogenase complex, and cellular metabolic status by measuring ATP levels. In comparison to glucose, supply of exogenous pyruvate restored the morphological integrity of post-ischemic astrocytes and prevented gliosis. Pyruvate prevented the cell death of post-ischemic astrocytes by inhibiting the leakage of lactate dehydrogenase, decreasing the redox ratio and restraining the activation of apoptotic events such as release of mitochondrial cytochrome c and fragmentation of caspase-3 and PARP. This study also suggests that pyruvate may accelerate its own metabolism by increasing the activity of pyruvate dehydrogenase and thus restores the cellular ATP levels in post-ischemic astrocytes. Use of pyruvate as an alternate fuel substrate may provide a possibility for the novel therapeutic approach to the treatment of cerebral ischemia.
 ...
PMID:Pyruvate ameliorates post ischemic injury of rat astrocytes and protects them against PARP mediated cell death. 1460 78

Ischemic preconditioning confers cardiac protection during subsequent ischemia-reperfusion, in which protein kinase C (PKC) is believed to play an essential role, but controversial data exist concerning the PKC-delta isoform. In an accompanying study (26), we described metabolic changes in PKC-delta knockout mice. We now wanted to explore their effect on early preconditioning. Both PKC-delta(-/-) and PKC-delta(+/+) mice underwent three cycles of 5-min left descending artery occlusion/5-min reperfusion, followed by 30-min occlusion and 2-h reperfusion. Unexpectedly, preconditioning exaggerated ischemia-reperfusion injury in PKC-delta(-/-) mice. Whereas ischemic preconditioning increased superoxide anion production in PKC-delta(+/+) hearts, no increase in reactive oxygen species was observed in PKC-delta(-/-) hearts. Proteomic analysis of preconditioned PKC-delta(+/+) hearts revealed profound changes in enzymes related to energy metabolism, e.g., NADH dehydrogenase and ATP synthase, with partial fragmentation of these mitochondrial enzymes and of the E(2) component of the pyruvate dehydrogenase complex. Interestingly, fragmentation of mitochondrial enzymes was not observed in PKC-delta(-/-) hearts. High-resolution NMR analysis of cardiac metabolites demonstrated a similar rise of phosphocreatine in PKC-delta(+/+) and PKC-delta(-/-) hearts, but the preconditioning-induced increase in phosphocholine, alanine, carnitine, and glycine was restricted to PKC-delta(+/+) hearts, whereas lactate concentrations were higher in PKC-delta(-/-) hearts. Taken together, our results suggest that reactive oxygen species generated during ischemic preconditioning might alter mitochondrial metabolism by oxidizing key mitochondrial enzymes and that metabolic adaptation to preconditioning is impaired in PKC-delta(-/-) hearts.
 ...
PMID:Ischemic preconditioning exaggerates cardiac damage in PKC-delta null mice. 1527 9

The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2 60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2, which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate.
 ...
PMID:Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. 1731 Feb 82

Hibernating myocardium is accompanied by a downregulation in energy utilization that prevents the immediate development of ischemia during stress at the expense of an attenuated level of regional contractile function. We used a discovery based proteomic approach to identify novel regional molecular adaptations responsible for this phenomenon in subendocardial samples from swine instrumented with a chronic LAD stenosis. After 3 months (n=8), hibernating myocardium was present as reflected by reduced resting LAD flow (0.75+/-0.14 versus 1.19+/-0.14 mL x min(-1) x g(-1) in remote) and wall thickening (1.93+/-0.46 mm versus 5.46+/-0.41 mm in remote, P<0.05). Regionally altered proteins were quantified with 2D Differential-in-Gel Electrophoresis (2D-DIGE) using normal myocardium as a reference with identification of candidates using MALDI-TOF mass spectrometry. Hibernating myocardium developed a significant downregulation of many mitochondrial proteins and an upregulation of stress proteins. Of particular note, the major entry points to oxidative metabolism (eg, pyruvate dehydrogenase complex and Acyl-CoA dehydrogenase) and enzymes involved in electron transport (eg, complexes I, III, and V) were reduced (P<0.05). Multiple subunits within an enzyme complex frequently showed a concordant downregulation in abundance leading to an amplification of their cumulative effects on activity (eg, "total" LAD PDC activity was 21.9+/-3.1 versus 42.8+/-1.9 mU, P<0.05). After 5-months (n=10), changes in mitochondrial and stress proteins persisted whereas cytoskeletal proteins (eg, desmin and vimentin) normalized. These data indicate that the proteomic phenotype of hibernating myocardium is dynamic and has similarities to global changes in energy substrate metabolism and function in the advanced failing heart. These proteomic changes may limit oxidative injury and apoptosis and impact functional recovery after revascularization.
 ...
PMID:Persistent regional downregulation in mitochondrial enzymes and upregulation of stress proteins in swine with chronic hibernating myocardium. 1817 69


<< Previous 1 2 3 Next >>