Actin is oxidized during myocardial ischemia

Powell, Saul R.; Gurzenda, Ellen; Wahezi, Sayed E.

doi:10.1016/s0891-5849(01)00514-7

Cited by 75 publications

(47 citation statements)

References 23 publications

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“…12 Oxidative damage to 19S regulatory particles has not previously been examined in the setting of myocardial ischemia. These studies demonstrate that at least one critical ATPase subunit is subject to significant oxidative carbonylation to a degree consistent with what we 5,23 have previously reported for actin and other proteins. Identification of these subunits was supported by a combination of immunoprecipitation, 1D and 2D gel electrophoresis, and mass spectrometry.…”

Section: Ischemic Preconditioning Preserves Postischemic Proteasome Fsupporting

confidence: 91%

Myocardial Ischemic Preconditioning Preserves Postischemic Function of the 26S Proteasome Through Diminished Oxidative Damage to 19S Regulatory Particle Subunits

Divald

Kivity

Wang

et al. 2010

Circulation Research

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Rationale: The ubiquitin proteasome system (UPS) becomes dysfunctional as a result of ischemia/reperfusion (I/R), which may lead to dysregulation of signaling pathways. Ischemic preconditioning (IPC) may prevent dysregulation by preventing UPS dysfunction through inhibition of oxidative damage. Objective: Examine the hypothesis that early IPC preserves postischemic UPS function thus facilitating prosurvival signaling events. Methods and Results: I/R decreased proteasome chymotryptic activity by 50% in isolated rat heart and an in vivo murine left anterior descending coronary artery occlusion model. Following IPC, proteasome activity was decreased 25% (P<0.05) in isolated heart and not different from baseline in the murine model. Enriched 26S proteasome was prepared and analyzed for protein carbonyl content. Increased (P<0.05) carbonylation in a 53-kDa band following I/R was diminished by IPC. Immunoprecipitation studies indicated that the 53-kDa carbonylation signal was of proteasomal origin. Two-dimensional gel electrophoresis resolved the 53-kDa band into spots analyzed by liquid chromatography/tandem mass spectrometry containing Rpt3/Rpt5 both of which could be immunoprecipitated conjugated to dinitrophenylhydrazine (DNPH). Higher amounts of DNPH-tagged Rpt5 were immunoprecipitated from the I/R samples and less from the IPC samples. I/R increased Bax levels by 63% (P<0.05) which was decreased by IPC. Lactacystin (lac) pretreatment of preconditioned hearts increased Bax by 140% (P<0.05) and also increased ubiquitinated proteins. Pretreatment of hearts with a proteasome inhibitor reversed the effects of IPC on postischemic Rpt5 carbonylation, cardiac function, morphology and morphometry, and ubiquitinated and signaling proteins. Conclusions: These studies suggest that IPC protects function of the UPS by diminishing oxidative damage to 19S regulatory particle subunits allowing this complex to facilitate degradation of proapoptotic proteins. (Circ Res. 2010;106:1829-1838.)Key Words: ischemia Ⅲ reperfusion Ⅲ preconditioning Ⅲ ubiquitin-proteasome system I schemic preconditioning (IPC) decreases the vulnerability of the myocardium to longer durations of ischemia as a result of preischemic exposure to short ischemic bursts as evidenced by improved postischemic hemodynamic function and reduced markers of injury. 1 The mechanisms involved with IPC has been the subject of intense research and the earlier steps appear to involve signaling changes resulting in opening of the inward mitochondrial K ATP channels 2 and prevention of opening of the mitochondrial permeability transition pore. 3 These early changes have been linked to decreased release of cytochrome c with diminished cellular apoptosis, 3 as well as decreased production of oxidative species. 4 We have shown that a downstream effect of preconditioning is diminished myocardial oxidative injury. 5 One later effect of IPC is decreased levels of certain proapoptotic proteins, such as Bax. 6 Earlier studies focused on diminished upregulation of these proteins t...

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Section: Ischemic Preconditioning Preserves Postischemic Proteasome Fsupporting

confidence: 91%

Myocardial Ischemic Preconditioning Preserves Postischemic Function of the 26S Proteasome Through Diminished Oxidative Damage to 19S Regulatory Particle Subunits

Divald

Kivity

Wang

et al. 2010

Circulation Research

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“…The complex modifications induced by ROS on muscle actin are characterised by severe disruption of the actin filaments, hampering their interaction with the myosin protein [38], thus suggesting that oxidation of contractile actin may contribute to muscle dysfunction in these models [36,38]. In our study, although muscle actin levels did not differ between COPD patients and controls, disruption of the contractile actin in the diaphragms of the severe patients cannot be ruled out.…”

Section: Diaphragm Carbonylated Proteinscontrasting

confidence: 55%

“…Several studies have already demonstrated oxidation of the cytoskeletal protein actin in different models [36,37]. The complex modifications induced by ROS on muscle actin are characterised by severe disruption of the actin filaments, hampering their interaction with the myosin protein [38], thus suggesting that oxidation of contractile actin may contribute to muscle dysfunction in these models [36,38].…”

Section: Diaphragm Carbonylated Proteinsmentioning

confidence: 99%

Oxidised proteins and superoxide anion production in the diaphragm of severe COPD patients

Minguella²,

et al. 2009

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In the diaphragms of chronic obstructive pulmonary disease (COPD) patients, the nature of oxidatively modified proteins and superoxide anion production were explored.Diaphragm specimens were obtained through thoracotomy because of localised lung lesions in COPD patients (16 severe and eight moderate) and 10 control subjects. Lung and respiratory muscle functions were evaluated. Oxidised proteins were identified using immunoblotting and mass spectrometry. Protein and activity levels of the identified proteins were determined using immunoblotting and activity assays. Lucigenin-derived chemiluminescence signals in a luminometer were used to determine superoxide anion levels in muscle compartments (mitochondria, membrane and cytosol) using selective inhibitors.In severe COPD patients compared with controls, respiratory muscle function was impaired; creatine kinase, carbonic anhydrase III, actin and myosin were oxidised; myosin carbonylation levels were increased five-fold; creatine kinase content and activity and myosin protein were reduced; superoxide anion levels were increased in both mitochondria and membrane compartments; and the percentage of superoxide anion inhibition achieved by rotenone was significantly greater.In severe COPD patients, oxidation of diaphragm proteins involved in energy production and contractile performance is likely to partially contribute to the documented respiratory muscle dysfunction. Furthermore, generation of the superoxide anion was increased in the diaphragms of these patients.

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“…Actin isoforms are carbonylated both in vitro [37,38] and in vivo, e.g., in the skeletal muscles of a diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rat [41], in macrophages exposed to hyperoxia [42], in the septic diaphragm [43], and in synaptosomes oxidized by treatment with the 42-amino acid peptide, amyloid β-peptide [Aβ(1-42)] [44]. Actin carbonylation has been determined in human intestinal cells exposed to H 2 O 2 or HOCl and in colonic mucosa from Crohn's disease patients, where it is associated with the disruption of the actin cytoskeleton and the loss of the monolayer barrier function [45,46], as well as during reperfusion of the ischaemic rat heart [47] and in AD subjects [48].…”

Section: The Impact Of Carbonylation On Protein Functionmentioning

confidence: 99%

Protein carbonylation, cellular dysfunction, and disease progression

Dalle‐Donne

Aldini

Colombo

et al. 2006

Journal of Cellular and Molecular Medicine

728

545

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Carbonylation of proteins is an irreversible oxidative damage, often leading to a loss of protein function, which is considered a widespread indicator of severe oxidative damage and disease-derived protein dysfunction. Whereas moderately carbonylated proteins are degraded by the proteasomal system, heavily carbonylated proteins tend to form high-molecular-weight aggregates that are resistant to degradation and accumulate as damaged or unfolded proteins. Such aggregates of carbonylated proteins can inhibit proteasome activity. A large number of neurodegenerative diseases are directly associated with the accumulation of proteolysis-resistant aggregates of carbonylated proteins in tissues. Identification of specific carbonylated protein(s) functionally impaired and development of selective carbonyl blockers should lead to the definitive assessment of the causative, correlative or consequential role of protein carbonylation in disease onset and/or progression, possibly providing new therapeutic aproaches.

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Actin is oxidized during myocardial ischemia

Cited by 75 publications

References 23 publications

Myocardial Ischemic Preconditioning Preserves Postischemic Function of the 26S Proteasome Through Diminished Oxidative Damage to 19S Regulatory Particle Subunits

Myocardial Ischemic Preconditioning Preserves Postischemic Function of the 26S Proteasome Through Diminished Oxidative Damage to 19S Regulatory Particle Subunits

Oxidised proteins and superoxide anion production in the diaphragm of severe COPD patients

Protein carbonylation, cellular dysfunction, and disease progression

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