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

Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl-CoA to free CoA, thus stimulating the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of high-energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically, levocarnitine has been shown to have anti-ischemic properties. In small short-term studies, levocarnitine acts as an antianginal agent that reduces ST segment depression and left ventricular end-diastolic pressure. These short-term studies also show that levocarnitine releases the lactate of coronary artery disease patients subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6 g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia and reperfusion by (1) preventing the accumulation of long-chain acyl-CoA, which facilitates the production of free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative-induced damage to membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the myocardium of long-chain acyl-CoA; and (4) reducing the ischemia-induced apoptosis and the consequent remodeling of the left ventricle. Propionyl-L-carnitine is a carnitine derivative that has a high affinity for muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid transport into the mitochondria. Moreover, propionyl-L-carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-L-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-L-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-L-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.
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PMID:Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. 1559 Oct 5

Cardiac ischemia and reperfusion are associated with loss in the activity of the mitochondrial enzyme pyruvate dehydrogenase (PDH). Pharmacological stimulation of PDH activity improves recovery in contractile function during reperfusion. Signaling mechanisms that control inhibition and reactivation of PDH during reperfusion were therefore investigated. Using an isolated rat heart model, we observed ischemia-induced PDH inhibition with only partial recovery evident on reperfusion. Translocation of the redox-sensitive delta-isoform of protein kinase C (PKC) to the mitochondria occurred during reperfusion. Inhibition of this process resulted in full recovery of PDH activity. Infusion of the deltaPKC activator H2O2 during normoxic perfusion, to mimic one aspect of cardiac reperfusion, resulted in loss in PDH activity that was largely attributable to translocation of deltaPKC to the mitochondria. Evidence indicates that reperfusion-induced translocation of deltaPKC is associated with phosphorylation of the alphaE1 subunit of PDH. A potential mechanism is provided by in vitro data demonstrating that deltaPKC specifically interacts with and phosphorylates pyruvate dehydrogenase kinase (PDK)2. Importantly, this results in activation of PDK2, an enzyme capable of phosphorylating and inhibiting PDH. Thus, translocation of deltaPKC to the mitochondria during reperfusion likely results in activation of PDK2 and phosphorylation-dependent inhibition of PDH.
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PMID:Reperfusion-induced translocation of deltaPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation. 1596 16

The rate of cardiac fatty acid oxidation is regulated by the activity of carnitine palmitoyltransferase-I (CPT-I), which is inhibited by malonyl-CoA. We tested the hypothesis that the activity of the enzyme responsible for malonyl-CoA degradation, malonyl-CoA decarboxlyase (MCD), regulates myocardial malonyl-CoA content and the rate of fatty acid oxidation during demand-induced ischemia in vivo. The myocardial content of malonyl-CoA was increased in anesthetized pigs using a specific inhibitor of MCD (CBM-301106), which we hypothesized would result in inhibition of CPT-I, reduction in fatty acid oxidation, a reciprocal activation of glucose oxidation, and diminished lactate production during demand-induced ischemia. Under normal-flow conditions, treatment with the MCD inhibitor significantly reduced oxidation of exogenous fatty acids by 82%, shifted the relationship between arterial fatty acids and fatty acid oxidation downward, and increased glucose oxidation by 50%. Ischemia was induced by a 20% flow reduction and beta-adrenergic stimulation, which resulted in myocardial lactate production. During ischemia MCD inhibition elevated malonyl-CoA content fourfold, reduced free fatty acid oxidation rate by 87%, and resulted in a 50% decrease in lactate production. Moreover, fatty acid oxidation during ischemia was inversely related to the tissue malonyl-CoA content (r = -0.63). There were no differences between groups in myocardial ATP content, the activity of pyruvate dehydrogenase, or myocardial contractile function during ischemia. Thus modulation of MCD activity is an effective means of regulating myocardial fatty acid oxidation under normal and ischemic conditions and reducing lactate production during demand-induced ischemia.
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PMID:Malonyl-CoA decarboxylase inhibition suppresses fatty acid oxidation and reduces lactate production during demand-induced ischemia. 1610 Feb 46

Ranolazine is a metabolic modulator that is being developed by CV Therapeutics (CVT), under license from Roche (formerly Syntex), as a potential treatment for angina. In August 1999, the first of two pivotal phase III clinical trials in patients with stable angina was completed. In August 1999, CVT announced initial results from this trial, designated the MARISA trial, of ranolazine in patients with stable angina. At each of the three doses studied, ranolazine significantly increased patients' treadmill exercise duration compared to placebo, the primary endpoint for this trial. MARISA (monotherapy assessment of ranolazine in stable angina) was a randomized, double-blind, placebo-controlled trial of a sustained release formulation of ranolazine used in 175 patients who were not receiving other anti-anginal drugs. Compared to placebo, ranolazine taken bid at doses of 500, 1000 or 1500 mg significantly increased exercise duration at trough plasma concentrations, which occur at about 12 h after the previous dose. In addition, two key secondary endpoints, exercise time to onset of angina and exercise time to the electrocardiographic appearance of ischemia were also significantly increased by ranolazine compared to placebo at all three doses. The company plans on presenting additional data at a major medical conference, including safety and tolerability data, which are still under analysis. In July 1999 CVT initiated its second phase III trial. The CARISA trial (combination assessment of ranolazine in stable angina) is a randomized, double-blind, placebo-controlled trial of ranolazine used in combination with other anti-anginal drugs, in approximately 450 patients. The primary endpoint for this trial, duration of exercise on a treadmill, is identical to that used in phase II clinical trials. The CARISA trial, along with the pivotal phase III MARISA trial which completed treatment in June 1999, is expected to form the basis of the company's NDA submission to the FDA. In June 1999, results of a randomized, double-blind, placebo-controlled phase II study of ranolazine in chronic stable angina pectoris were published in the July 1, 1999 issue of the American Journal of Cardiology. The study of 312 patients demonstrated that ranolazine may increase exercise time in chronic stable angina patients. The results also indicate that there may be no change in heart rate or blood pressure among any of the ranolazine dosing regimens. In January 1999, CVT received regulatory clearance in Canada, the Czech Republic and Poland and initiated its first pivotal phase III trial for ranolazine in these countries. These new clinical trial centers complement the US centers enrolling American patients. The compound allows maintenance of energy output by muscle cells by improving oxygen metabolism to make the heart pump more efficiently. Ranolazine may be especially useful in angina patients in whom other therapies are ineffective. Clinical studies suggest that ranolazine lowers the heart's demand for oxygen, by increasing its ability to use carbohydrate rather than fat as a fuel. This is thought to be due to activation of pyruvate dehydrogenase, and also by modulating the activities of L-type calcium channels. This is achieved without reducing heart rate or blood pressure, or impairing pumping ability. In August 1998, CVT signed an agreement with Catalytica Pharmaceuticals, which will manufacture specified quantities of ranolazine for use in clinical trials.
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PMID:Ranolazine (Roche Bioscience). 1611 67

We used proteomics to detect regional differences in protein expression levels from mitochondrial fractions of control, ischemia-reperfusion (IR), and ischemic preconditioned (IPC) rabbit hearts. Using 2-DE, we identified 25 mitochondrial proteins that were differentially expressed in the IR heart compared with the control and IPC hearts. For three of the spots, the expression patterns were confirmed by Western blotting analysis. These proteins included 3-hydroxybutyrate dehydrogenase, prohibitin, 2-oxoglutarate dehydrogenase, adenosine triphosphate synthases, the reduced form of nicotinamide adenine dinucleotide (NADH) oxidoreductase, translation elongation factor, actin alpha, malate dehydrogenase, NADH dehydrogenase, pyruvate dehydrogenase and the voltage-dependent anion channel. Interestingly, most of these proteins are associated with the mitochondrial respiratory chain and energy metabolism. The successful use of multiple techniques, including 2-DE, MALDI-TOF-MS and Western blotting analysis demonstrates that proteomic analysis provides appropriate means for identifying cardiac markers for detection of ischemia-induced cardiac injury.
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PMID:Potential biomarkers for ischemic heart damage identified in mitochondrial proteins by comparative proteomics. 1640 59

The aim of the present study was to assess the effect of post ictal administration of the pyrrolopyrimidine lipid peroxidation inhibitor, U-101033E, on infarct volume and neuronal and astrocytic metabolism in rats with transient middle cerebral artery occlusion (MCAO). Rats were subjected to 120 min of MCAO followed by 140 min of reperfusion and randomly assigned to control (n=17) or U-101033E treatment (n=16). Drug infusion started 5 min after MCAO and lasted 220 min with a 15 min interruption during the reperfusion procedure. Sixteen rats underwent diffusion weighted imaging 260 min after ictus, from which the apparent diffusion coefficient (ADC) was determined. Seventeen rats received an iv bolus injection of [1-13C]glucose and [1,2-13C]acetate 245 min after ictus. Tissue extracts from two brain regions representing penumbra and ischemic core were analyzed with 13C NMRS and HPLC. U-101033E did not affect the volume of ischemic tissue estimated from the ADC maps. In the penumbra, U-101033E specifically decreased mitochondrial pyruvate metabolism via both pyruvate dehydrogenase and pyruvate carboxylase pathways. Thus, U-101033E impaired both neuronal and astrocytic mitochondrial pyruvate metabolism. At the same time anaerobic glucose usage was increased, leading to increased lactate labeling and content. Also alanine labeling was increased. The data do not support lactate as an important substrate for neuronal mitochondria in ischemia-reperfusion. A similar pattern of reduced mitochondrial pyruvate metabolism and increased cytosolic pyruvate metabolism was found in the irreversibly damaged ischemic core. The present study highlights the importance of other outcome measures than ischemic tissue volume for evaluation of drug efficacy in animal models, which in turn could increase the likelihood of success in clinical trials.
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PMID:Effect of the pyrrolopyrimidine lipid peroxidation inhibitor U-101033E on neuronal and astrocytic metabolism and infarct volume in rats with transient middle cerebral artery occlusion. 1724 1

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.
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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.
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PMID:Persistent regional downregulation in mitochondrial enzymes and upregulation of stress proteins in swine with chronic hibernating myocardium. 1817 69

Mitochondrial function in the brain of mouse trisomy 16, an animal model of Down syndrome with accelerated neuron death, was studied in isolated cortex mitochondria. Using an oxygen-sensitive Clarke electrode, a selective 16% decrease in respiration was detected with the Complex I substrates malate and glutamate but not with the Complex II substrate succinate. Western blotting revealed a 20% decrease in the 20 kDa subunit of Complex I in Ts16 brain cortex homogenates with no significant decrease in marker proteins for the other complexes of the electron transport chain. Although no differences in H(2)O(2) production or maximal calcium uptake were detected in the Ts16 mitochondria, there was an 18% decrease in pyruvate dehydrogenase levels, a change associated with oxidative stress in ischemia. These results are similar to those found in Parkinson's disease suggesting some neurodegenerative diseases may have mitochondrial pathology as a common step.
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PMID:Mitochondrial dysfunction in mouse trisomy 16 brain. 1806 Nov 51

Pyruvate dehydrogenase complex (PDC) plays an important role in energy homeostasis in the heart by catalyzing the oxidative decarboxylation of pyruvate derived primarily from glucose and lactate. Because various pathophysiological states can markedly alter cardiac glucose metabolism and PDC has been shown to be altered in response to chronic ischemia, cardiac physiology of a mouse model with knockout of the alpha-subunit of the pyruvate dehydrogenase component of PDC in heart/skeletal muscle (H/SM-PDCKO) was investigated. H/SM-PDCKO mice did not show embryonic lethality and grew normally during the preweaning period. Heart and skeletal muscle of homozygous male mice had very low PDC activity (approximately 5% of wild-type), and PDC activity in these tissues from heterozygous females was approximately 50%. Male mice did not survive for >7 days after weaning on a rodent chow diet. However, they survived on a high-fat diet and developed left ventricular hypertrophy and reduced left ventricular systolic function compared with wild-type male mice. The changes in the heterozygote female mice were of lesser severity. The deficiency of PDC in H/SM-PDCKO male mice greatly compromises the ability of the heart to oxidize glucose for the generation of energy (and hence cardiac function) and results in cardiac pathological changes. This mouse model demonstrates the importance of glucose oxidation in cardiac energetics and function under basal conditions.
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PMID:Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice. 1864 Dec 70


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