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)

Aldose reductase has been implicated in the etiology of diabetic complications, atherosclerosis, and ischemia-reperfusion injury. Aldose reductase inhibitors are known to have species-dependent differences in biotransformation enzyme induction. Whether aldose reductase inhibitors, which have antioxidant potential, alter the oxidative stress pathway is unknown. This study has determined whether four daily ip treatments of either low (10 mg/kg) or high (50 mg/kg) doses of AL-1576 or AL-4114 alter the activities of the antioxidant defense enzymes catalase, glutathione reductase, glutathione peroxidase, superoxide dismutase, and the concentrations of reduced and oxidized glutathione in livers of normal rats and rabbits. There was no change in the concentration of thiobarbituric acid reactive substances in either rat or rabbit livers, indicating that lipid peroxidation was not increased by any treatment. Hepatic catalase, superoxide dismutase, and glutathione peroxidase activities and concentrations of reduced and oxidized glutathione were not significantly altered in rat, though glutathione reductase activity was increased after high doses of both drugs. However, in rabbit liver, glutathione reductase activity decreased in a dose-dependent manner after AL-4114 treatment, while superoxide dismutase and glutathione peroxidase activities decreased only after the low dose of AL-4114. Although AL-4114 and AL-1576 did not directly generate increased lipid peroxidation within normal rat and rabbit livers, some of the enzymes responsible for oxidative defense were altered, particularly in rabbit livers.
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PMID:Effects of aldose reductase inhibitors on antioxidant defense in rat and rabbit liver. 1065 32

Aldose reductase, a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications in diabetes. Despite recent studies from our laboratory demonstrating protection of ischemic hearts by an aldose reductase inhibitor, the presence and influence of aldose reductase in cardiac tissue remain unknown. Our goal in this study was to isolate and characterize the kinetic properties of cardiac aldose reductase, as well as to study the impact of flux via this enzyme on glucose metabolism and contractile function in hearts subjected to ischemia-reperfusion. Results demonstrate that ischemia increases myocardial aldose reductase activity and that these increases are, in part, due to activation by nitric oxide. The kinetic parameter of cardiac aldose reductase (Kcat) was significantly higher in ischemic tissues. Aldose reductase inhibition increased glycolysis and glucose oxidation. Aldose reductase inhibited hearts, when subjected to ischemia/reperfusion, exhibited less ischemic injury and was associated with lower lactate/pyruvate ratios (a measure of cytosolic NADH/NAD+), greater tissue content of adenosine triphosphate, and improved cardiac function. These findings indicate that aldose reductase is a component of ischemic injury and that pharmacological inhibitors of aldose reductase present a novel adjunctive approach for protecting ischemic hearts.
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PMID:Aldose reductase activation is a key component of myocardial response to ischemia. 1177 43

Aldose reductase (AR), a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications of diabetes. Recently, we demonstrated that aldose reductase is a component of myocardial ischemic injury and that inhibitors of this enzyme protect rat hearts from ischemia-reperfusion injury. To rigorously test the effect of aldose reductase on myocardial ischemia-reperfusion injury, we used transgenic mice broadly overexpressing human aldose reductase (ARTg) driven by the major histocompatibility complex I promoter. Hearts from these ARTg or littermate mice (WT) (n=6 in each group) were isolated, perfused under normoxic conditions, then subjected to 50 min of severe low flow ischemia followed by 60 min of reperfusion. Creatine kinase (CK) release (a marker of ischemic injury) was measured during reperfusion; left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and ATP were measured throughout the protocol. CK release was significantly greater in ARTg mice compared with the WT mice. LVDP recovery was significantly reduced in ARTg mice compared with the WT mice. Furthermore, ATP content was higher in WT mice compared with ARTg mice during ischemia and reperfusion. Infarct size measured by staining techniques and myocardial damage evaluated histologically were also significantly worse in ARTg mice hearts than in controls. Pharmacological inhibition of aldose reductase significantly reduced ischemic injury and improved functional recovery in ARTg mice. These data strongly support key roles for AR in ischemic injury and impairment of functional and metabolic recovery after ischemia. We propose that interventions targeting AR may provide a novel adjunctive approach to protect ischemic myocardium.
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PMID:Central role for aldose reductase pathway in myocardial ischemic injury. 1528 19

Aldose reductase (AR) reduces cytotoxic aldehydes and glutathione conjugates of aldehydes derived from lipid peroxidation. Its inhibition has been shown to increase oxidative injury and abolish the late phase of ischemic preconditioning. However, the mechanisms by which ischemia regulates AR activity remain unclear. Herein, we report that rat hearts subjected to ischemia, in situ or ex vivo, display a 2-4-fold increase in AR activity. The AR activity was not further enhanced by reperfusion. Activation increased Vmax of the enzyme without affecting the Km and decreased the sensitivity of the enzyme to inhibition by sorbinil. Enzyme activation could be prevented by pretreating the hearts with the radical scavenging thiol, N-(2-mercaptoproprionyl)glycine or the superoxide dismutase mimetic, Tiron, or by treating homogenates with dithiothreitol. In vitro, the recombinant enzyme was activated upon treatment with H2O2 and the activated, but not the native enzyme, formed a covalent adduct with the sulfenic acid-specific reagent dimedone. The enzyme activity in the ischemic, but not the nonischemic heart homogenates was inhibited by dimedone. Separation of proteins from hearts subjected to coronary occlusion by two-dimensional electrophoresis and subsequent matrix-assisted laser desorption ionization time-of-flight/mass spectrometry analysis revealed the formation of sulfenic acids at Cys-298 and Cys-303. These data indicate that reactive oxygen species formed in the ischemic heart activate AR by modifying its cysteine residues to sulfenic acids.
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PMID:Redox activation of aldose reductase in the ischemic heart. 1656 3

Aldose reductase (AR) has been implicated in the pathogenesis of diabetic complications, although the clinical efficacy of AR inhibitors has not been clearly proven. To clarify the pathophysiological role of AR in the heart, we investigated effects of AR inhibitors applied either during the pre-ischemic phase, or during the post-ischemic reperfusion phase on ischemia-reperfusion injury in isolated heart from transgenic mice overexpressing human AR. On reperfusion following global ischemia, transgenic mouse hearts exhibited lower left developed pressure, increased release of creatine kinase, and lower ATP content compared with their littermates. When inhibitors of AR were applied during the pre-ischemic phase, they significantly improved deranged cardiac function, creatine kinase release, and ATP content. On the other hand, inhibition of AR during the post-ischemic reperfusion phase did not affect cardiac performance and ATP content, but it significantly attenuated creatine kinase release and the level of thiobarbiturate-reactive substances in transgenic mouse hearts. These results suggest a dual role of AR in ischemia-reperfusion injury. Inhibition of AR during ischemia preserved generation of ATP via glycolysis, whereas inhibition during the reperfusion phase reduced myocardial injury by attenuating oxidative stress elicited by ischemic insult and reoxygenation.
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PMID:Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism. 1693 55

Aldose reductase (AR) catalyzes the reduction of several aldehydes ranging from lipid peroxidation products to glucose. The activity of AR is increased in the ischemic heart due to oxidation of its cysteine residues, but the underlying mechanisms remain unclear. To examine signaling mechanisms regulating AR activation, we studied the role of nitric oxide (NO). Treatment with the NO synthase (NOS) inhibitor, N-nitro-l-arginine methyl ester prevented ischemia-induced AR activation and myocardial sorbitol accumulation in rat hearts subjected to global ischemia ex vivo or coronary ligation in situ, whereas inhibition of inducible NOS and neuronal NOS had no effect. Activation of AR in the ischemic heart was abolished by pretreatment with peroxynitrite scavengers hesperetin or 5, 10, 15, 20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron [III]. Site-directed mutagenesis and electrospray ionization mass spectrometry analyses showed that Cys-298 of AR was readily oxidized to sulfenic acid by peroxynitrite. Treatment with bradykinin and insulin led to a phosphatidylinositol 3-kinase (PI3K)-dependent increase in the phosphorylation of endothelial NOS at Ser-1177 and, even in the absence of ischemia, was sufficient in activating AR. Activation of AR by bradykinin and insulin was reversed upon reduction with dithiothreitol or by inhibiting NOS or PI3K. Treatment with AR inhibitors sorbinil or tolrestat reduced post-ischemic recovery in the rat hearts subjected to global ischemia and increased the infarct size when given before ischemia or upon reperfusion. These results suggest that AR is a cardioprotective protein and that its activation in the ischemic heart is due to peroxynitrite-mediated oxidation of Cys-298 to sulfenic acid via the PI3K/Akt/endothelial NOS pathway.
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PMID:Role of nitric oxide in regulating aldose reductase activation in the ischemic heart. 1822 94

Aldose reductase (AR) is a multi-functional AKR (AKR1B1) that catalyzes the reduction of a wide range of endogenous and xenobiotic aldehydes and their glutathione conjugates with high efficiency. Previous studies from our laboratory show that AR protects against myocardial ischemia-reperfusion injury, however, the mechanisms by which it confers cardioprotection remain unknown. Because AR metabolizes aldehydes generated from lipid peroxidation, we tested the hypothesis that it protects against ischemic injury by preventing ER stress induced by excessive accumulation of aldehyde-modified proteins in the ischemic heart. In cell culture experiments, exposure to model lipid peroxidation aldehydes-4-hydroxy-trans-2-nonenal (HNE), 1-palmitoyl-2-oxovaleroyl phosphatidylcholine (POVPC) or acrolein led to an increase in the phosphorylation of ER stress markers PERK and eIF2-alpha and an increase in ATF3. The reduced metabolite of POVPC 1-palmitoyl-2-hydroxyvaleroyl phosphatidylcholine (PHVPC) was unable to stimulate JNK phosphorylation. No increase in phospho-eIF2-alpha, ATF3 or phospho-PERK was observed in cells treated with the reduced HNE metabolite 1,4-dihydroxynonenol (DHN). Lysates prepared from isolated perfused mouse hearts subjected to 15 min of global ischemia followed by 30 min of reperfusion ex vivo showed greater phosphorylation of PERK and eIF2-alpha than hearts subjected to aerobic perfusion alone. Ischemia-induced increases in phospho-PERK and phospho-eIF2-alpha were diminished in the hearts of cardiomyocyte-specific transgenic mice overexpressing the AR transgene. These observations support the notion that by removing aldehydic products of lipid peroxidation, AR decreases ischemia-reperfusion injury by diminishing ER stress.
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PMID:Aldose reductase decreases endoplasmic reticulum stress in ischemic hearts. 1904 36

Aldose reductase (AR), the first enzyme in the polyol pathway, has been implicated in a wide variety of physiological and pathological functions, such as diabetic vascular and neural complications. It is known that diabetes mellitus can exacerbate brain and retina damage after ischemic injuries. However, the underlying mechanisms are not clear. In the present study, we made use of db/db mice with an AR null mutation (AR(-/-)db/db) to understand better the role of AR in the pathogenesis of brain and retina ischemic injuries under diabetic conditions. Cerebral and retinal ischemia was induced by transient middle cerebral artery occlusion in control and diabetic mice either with or without an AR null mutation. Mice were evaluated for neurological deficits after 30 min of ischemia and 23.5 hr of reperfusion. Our results showed that the diabetic db/db mice had significantly more severe neurological deficit and larger brain infarct size than the nondiabetic mice. Compared with wild-type db/db mice, the AR(-/-)db/db mice had significantly lower neurological scores, smaller brain infarct areas, and less hemispheric brain swelling. Retinal swelling was also significantly decreased in the AR(-/-)db/db mice. Less swelling in the brain and retina of the AR(-/-)db/db mice correlated with less expression of the water channel aquaporin 4. Taken together, these data clearly show that deletion of AR leads to less severe brain and retinal ischemic injuries in the diabetic db/db mouse. The present study indicates that inhibition of AR in diabetics may protect against damage in the brain and retina following ischemic reperfusion injury.
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PMID:More severe type 2 diabetes-associated ischemic stroke injury is alleviated in aldose reductase-deficient mice. 2014 23

Hyperglycemia and reduced insulin actions affect many biological processes. One theory is that aberrant metabolism of glucose via several pathways including the polyol pathway causes cellular toxicity. Aldose reductase (AR) is a multifunctional enzyme that reduces aldehydes. Under diabetic conditions AR converts glucose into sorbitol, which is then converted to fructose. This article reviews the biology and pathobiology of AR actions. AR expression varies considerably among species. In humans and rats, the higher level of AR expression is associated with toxicity. Flux via AR is increased by ischemia and its inhibition during ischemia reperfusion reduces injury. However, similar pharmacological effects are not observed in mice unless they express a human AR transgene. This is because mice have much lower levels of AR expression, probably insufficient to generate toxic byproducts. Human AR expression in LDL receptor knockout mice exacerbates vascular disease, but only under diabetic conditions. In contrast, a recent report suggests that genetic ablation of AR increased atherosclerosis and increased hydroxynonenal in arteries. It was hypothesized that AR knockout prevented reduction of toxic aldehydes. Like many in vivo effects found in genetically manipulated animals, interpretation requires the reproduction of human-like physiology. For AR, this will require tissue specific expression of AR in sites and at levels that approximate those in humans.
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PMID:Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental model. 2046 86

Aldose reductase (AR) is a multifunctional enzyme that catalyzes the reduction of glucose and lipid peroxidation-derived aldehydes. During myocardial ischemia, the activity of AR is increased due to the oxidation of its cysteine residues to sulfenic acids. It is not known, however, whether the activated, sulfenic form of the protein (AR-SOH) is converted back to its reduced, unactivated state (AR-SH). We report here that in perfused mouse hearts activation of AR during 15 min of global ischemia is completely reversed by 30 min of reperfusion. During reperfusion, AR-SOH was converted to a mixed disulfide (AR-SSG). Deactivation of AR and the appearance of AR-SSG during reperfusion were delayed in hearts of mice lacking glutathione S-transferase P (GSTP). In vitro, GSTP accelerated glutathiolation and inactivation of AR-SOH. Reduction of AR-SSG to AR-SH was facilitated by glutaredoxin (GRX). Ischemic activation of AR was increased in GRX-null hearts but was attenuated in the hearts of cardiospecific GRX transgenic mice. Incubation of AR-SSG with GRX led to the regeneration of the reduced form of the enzyme. In ischemic cardiospecific AR transgenic hearts, AR was co-immunoprecipitated with GSTP, whereas in reperfused hearts, the association of AR with GRX was increased. These findings suggest that upon reperfusion of the ischemic heart AR-SOH is converted to AR-SSG via GSTP-assisted glutathiolation. AR-SSG is then reduced by GRX to AR-SH. Sequential catalysis by GSTP and GRX may be a general redox switching mechanism that regulates the reduction of protein sulfenic acids to cysteines.
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PMID:Postischemic deactivation of cardiac aldose reductase: role of glutathione S-transferase P and glutaredoxin in regeneration of reduced thiols from sulfenic acids. 2053 86


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