4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion injury of the myocardium

Blasig, Ingolf E.; Grune, T; Schönheit, Katrin; Rohde, E; Jakstadt, Manuela; Haseloff, Reiner F.; Siems, Werner

doi:10.1152/ajpheart.1995.269.1.h14

Cited by 63 publications

(73 citation statements)

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“…22 Reoxygenation in the heart is known to elevate the levels of both HNE and protein carbonyl. 23,24 Using a dual fluorescence staining approach, we were able to confirm that exposure to hyperoxia indeed enhances cellular oxidant production ( Figure 1H). …”

Section: Resultsmentioning

confidence: 80%

Oxygen Sensing by Primary Cardiac Fibroblasts

Roy

Khanna

Bickerstaff

et al. 2003

Circulation Research

131

120

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Abstract-In mammalian organs under normoxic conditions, O 2 concentration ranges from 12% to Ͻ0.5%, with O 2 Ϸ14%in arterial blood and Ͻ10% in the myocardium. During mild hypoxia, myocardial O 2 drops to Ϸ1% to 3% or lower. In response to chronic moderate hypoxia, cells adjust their normoxia set point such that reoxygenation-dependent relative elevation of PO 2 results in perceived hyperoxia. These effects were independent of NADPH oxidase function. CFs exposed to high O 2 exhibited higher levels of reactive oxygen species production. The molecular signature response to perceived hyperoxia included (1) induction of p21, cyclin D1, cyclin D2, cyclin G1, Fos-related antigen-2, and transforming growth factor-␤1, (2) lowered telomerase activity, and (3) Key Words: redox Ⅲ free radicals Ⅲ heart Ⅲ cell culture C ellular O 2 concentrations are maintained within a narrow range (normoxia) because of the risk of oxidative damage from excess O 2 (hyperoxia) and of metabolic demise from insufficient O 2 (hypoxia). 1 PO 2 ranges from 90 to Ͻ3 mm Hg in mammalian organs under normoxic conditions, with arterial PO 2 of Ϸ100 mm Hg or Ϸ14% O 2 . 2 Thus, "normoxia" for cells is a variable that is dependent on the specific localization of the cell in organs and functional status of the specific tissue. O 2 sensing is required to adjust to physiological or pathophysiological variations in PO 2 . Current work in this field is almost exclusively focused on the study of hypoxia. Reoxygenation, on the other hand, has been mostly investigated in the context of oxidative injury. Over 25 years ago, it was observed that PO 2 beyond the comfort of the "perceived normoxic range" is a significant stressor, leading to growth arrest. 3 The molecular bases of such observations remain to be characterized in light of current knowledge of signal transduction.During chronic hypoxia in the heart, cells adjust their normoxic set point such that the return to normoxic PO 2 after chronic hypoxia is perceived as relative hyperoxia. 4,5 We hypothesized that such challenge triggers changes in signal transduction processes. Although acute insult caused during reperfusion may be lethal to cells localized at the focus of insult, elevation of O 2 tension in the surrounding ischemic tissue triggers phenotypic changes in the surviving cells that may be associated with tissue remodeling.Ischemia in the heart results in a hypoxic area containing a central focus of near-zero O 2 pressure bordered by tissue with diminished but nonzero O 2 pressures. These border zones extend for several millimeters from the hypoxic core, with the O 2 pressures progressively increasing from the focus to the normoxic region. 6 Moderate hypoxia is associated with a 30% to 60% decrease (Ϸ1% to 3% O 2 ) in PO 2 . 7 Cardiac fibroblasts (CFs) are mainly responsible for the synthesis of major extracellular matrix (ECM) in the myocardium, including fibrillar collagen types I and III and fibronectin. More than 90% of the interstitial cells of the myocardium are fibroblasts, 8 which actively e...

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Section: Resultsmentioning

confidence: 80%

Oxygen Sensing by Primary Cardiac Fibroblasts

Roy

Khanna

Bickerstaff

et al. 2003

Circulation Research

131

120

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“…This paradoxical phenomenon, broadly termed ischemia/reperfusion injury, is accompanied by dramatic increases in tissue levels of free radicals as well as byproducts of lipid peroxidation (1)(2)(3)(4)(5)(6)(7)(8)(9). Due to the high reactivity of these species (10 -12), it has been proposed that free radical events play a key role in myocardial ischemia/reperfusion injury.…”

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confidence: 99%

Oxidative Modification and Inactivation of the Proteasome during Coronary Occlusion/Reperfusion

Bulteau¹,

Lundberg²,

Humphries³

et al. 2001

Journal of Biological Chemistry

334

257

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Restoration of blood flow to ischemic myocardial tissue results in an increase in the production of oxygen radicals. Highly reactive, free radical species have the potential to damage cellular components. Clearly, maintenance of cellular viability is dependent, in part, on the removal of altered protein. The proteasome is a major intracellular proteolytic system which degrades oxidized and ubiquitinated forms of protein. Utilizing an in vivo rat model, we demonstrate that coronary occlusion/ reperfusion resulted in declines in chymotrypsin-like, peptidylglutamyl-peptide hydrolase, and trypsin-like activities of the proteasome as assayed in cytosolic extracts. Analysis of purified 20 S proteasome revealed that declines in peptidase activities were accompanied by oxidative modification of the protein. We provide conclusive evidence that, upon coronary occlusion/ reperfusion, the lipid peroxidation product 4-hydroxy-2-nonenal selectively modifies 20 S proteasome ␣-like subunits iota, C3, and an isoform of XAPC7. Occlusion/ reperfusion-induced declines in trypsin-like activity were largely preserved upon proteasome purification. In contrast, loss in chymotrypsin-like and peptidylglutamyl-peptide hydrolase activities observed in cytosolic extracts were not evident upon purification. Thus, decreases in proteasome activity are likely due to both direct oxidative modification of the enzyme and inhibition of fluorogenic peptide hydrolysis by endogenous cytosolic inhibitory protein(s) and/or substrate(s). Along with inhibition of the proteasome, increases in cytosolic levels of oxidized and ubiquitinated protein(s) were observed. Taken together, our findings provide insight into potential mechanisms of coronary occlusion/reperfusion-induced proteasome inactivation and cellular consequences of these events.Restoration of coronary blood flow to previously ischemic cardiac tissue is often associated with declines in cardiac function, including myocardial stunning, ventricular arrhythmias, hemodynamic abnormalities, and, in the long term, development of heart failure (1, 2). This paradoxical phenomenon, broadly termed ischemia/reperfusion injury, is accompanied by dramatic increases in tissue levels of free radicals as well as byproducts of lipid peroxidation (1-9). Due to the high reactivity of these species (10 -12), it has been proposed that free radical events play a key role in myocardial ischemia/reperfusion injury. Nevertheless, mechanisms by which free radicals alter cardiac function have not been fully elucidated. Free radical modification of protein can alter and, in many cases, inhibit, protein activity (10 -15). In addition, oxidatively crosslinked protein(s) are resistant to proteolytic degradation (16 -20). Thus, the presence of oxidized protein could impact cellular function by changing the catalytic and/or regulatory properties of specific proteins and by placing abnormal demands on finite cellular volume. Clearly, the level of oxidatively modified protein reflects the balance between free radical damage and p...

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“…atherosclerosis, ischemia-reperfusion, or toxicity of anticancer drugs. While high concentrations of ␣,␤-unsaturated aldehydes or their adducts have been detected under these states (5,12,18,19), a causal relationship between aldehyde toxicity and oxidative stress remains to be established. However, to assess their contribution to specific pathological states and redox signaling, it is essential to identify the metabolism of these aldehydes.…”

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confidence: 99%

“…In cardiac myocytes, HNE causes metabolic inhibition, thiol oxidation, and generates pro-arrhythmic changes in cellular excitability (22). HNE-modified proteins have been detected in atherosclerotic plaques (12), and high concentrations of HNE have been measured in reperfused (18) or Adriamycin-treated (19) hearts.…”

mentioning

confidence: 99%

Metabolism of the Lipid Peroxidation Product, 4-Hydroxy-trans-2-nonenal, in Isolated Perfused Rat Heart

Srivastava¹,

Chandra²,

Wang³

et al. 1998

Journal of Biological Chemistry

221

176

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The metabolism of 4-hydroxy-trans-2-nonenal (HNE), an ␣,␤-unsaturated aldehyde generated during lipid peroxidation, was studied in isolated perfused rat hearts. High performance liquid chromatography separation of radioactive metabolites recovered from [ 3 H]HNE-treated hearts revealed four major peaks. Based on the retention times of synthesized standards, peak I, which accounted for 20% radioactivity administered to the heart, was identified to be due to glutathione conjugates of HNE. Peaks II and III, containing 2 and 37% radioactivity, were assigned to 1,4-dihydroxy-2-nonene (DHN) and 4-hydroxy-2-nonenoic acid, respectively. Peak IV was due to unmetabolized HNE. The electrospray ionization mass spectrum of peak I revealed two prominent metabolites with m/z values corresponding to [M ؉ H] ؉ of HNE and DHN conjugates with glutathione. The presence of 4-hydroxy-2-nonenoic acid in peak III was substantiated using gas chromatography-chemical ionization mass spectroscopy. When exposed to sorbinil, an inhibitor of aldose reductase, no GS-DHN was recovered in the coronary effluent, and treatment with cyanamide, an inhibitor of aldehyde dehydrogenase, attenuated 4-hydroxy-2-nonenoic acid formation. These results show that the major metabolic transformations of HNE in rat heart involve conjugation with glutathione and oxidation to 4-hydroxy-2-nonenoic acid. Further metabolism of the GS-HNE conjugate involves aldose reductasemediated reduction, a reaction catalyzed in vitro by homogenous cardiac aldose reductase.

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4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion injury of the myocardium

Cited by 63 publications

References 0 publications

Oxygen Sensing by Primary Cardiac Fibroblasts

Oxygen Sensing by Primary Cardiac Fibroblasts

Oxidative Modification and Inactivation of the Proteasome during Coronary Occlusion/Reperfusion

Metabolism of the Lipid Peroxidation Product, 4-Hydroxy-trans-2-nonenal, in Isolated Perfused Rat Heart

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