Identification of Protein Disulfide Isomerase as a Cardiomyocyte Survival Factor in Ischemic Cardiomyopathy

Severino, Anna; Campioni, Mara; Straino, Stefania; Salloum, Fadi N.; Schmidt, Nina; Herbrand, Ulrike; Frede, Stilla; Toietta, Gabriele; Rocco, Giuliana Di; Bussani, Rossana; Silvestri, Furio; Piro, Maddalena; Liuzzo, Giovanna; Biasucci, Luigi M.; Mellone, Pasquale; Feroce, Florinda; Capogrossi, Maurizio C.; Baldi, Feliciano; Fandrey, Joachim; Ehrmann, Michael; Crea, Filippo; Abbate, Antonio; Baldi, Alfonso

doi:10.1016/j.jacc.2007.06.006

Cited by 103 publications

(92 citation statements)

References 24 publications

(27 reference statements)

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“…Although the precise apoptotic mechanism mediated by CHOP is unknown, CHOP deficiency has been demonstrated to resist apoptotic stimulation from ER stress (21). Strikingly, as a member of the unfolded protein response, disulfide isomerase (PDI) was significantly increased to confer protection against ischemic damage (22). Tunicamycin was shown to increase the protein levels of PDI, which is necessary for appropriate protein folding and prevention of protein misfolding during stress (23).…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase-2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

Liao

Sun

Isse

et al. 2012

Mol Med

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Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been characterized as an important mediator of endogenous cytoprotection in the heart. This study was designed to examine the role of ALDH2 knockout (KO) in the regulation of cardiac function after endoplasmic reticulum (ER) stress. Wild-type (WT) and ALDH2 KO mice were subjected to a tunicamycin challenge, and the echocardiographic property was examined. Protein levels of six items-78 kDa glucose-regulated protein (GRP78), phosphorylation of eukaryotic initiation factor 2 subunit α (p-eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP), phosphorylation of Akt, p47 phox nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and 4-hydroxynonenal-were determined by using Western blot analysis. Cytotoxicity and apoptosis were estimated using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay and caspase-3 activity, respectively. ALDH2 deficiency exacerbated cardiac contractile dysfunction and promoted ER stress after ER stress induction, manifested by the changes of ejection fraction and fractional shortening. In vitro study revealed that tunicamycin significantly upregulated the levels of GRP78, p-eIF2α, CHOP, p47 phox NADPH oxidase and 4-hydroxynonenal, which was exacerbated by ALDH2 knockdown and abolished by ALDH2 overexpression, respectively. Overexpression of ALDH2 abrogated tunicamycin-induced dephosphorylation Akt. Inhibition of phosphatidylinositol 3-kinase using LY294002 did not affect ALDH2-conferred protection against ER stress, although LY294002 reversed the antiapoptotic action of ALDH2 associated with p47 phox NADPH oxidase. These results suggest a pivotal role of ALDH2 in the regulation of ER stress and ER stress-induced apoptosis. The protective role of ALDH2 against ER stress-induced cell death was probably mediated by Akt via a p47 phox NADPH oxidase-dependent manner. These findings indicate the critical role of ALDH2 in the pathogenesis of ER stress in heart disease.

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Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase-2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

Liao

Sun

Isse

et al. 2012

Mol Med

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“…factor, indicating that modulation of the ER thiol-disulfide system including E GSH (ER) confers therapeutic advantage (Tanaka et al, 2000;Severino et al, 2007;Walker et al, 2010;Wang et al, 2012). By developing a glutathione-responsive ER sensor, which allows an authentic estimate of E GSH (ER) in living cells, this study now offers an important tool to study these processes in vivo.…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

Endoplasmic reticulum: Reduced and oxidized glutathione revisited

Birk¹,

Meyer²,

Aller³

et al. 2013

Journal of Cell Science

138

152

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SummaryThe reducing power of glutathione, expressed by its reduction potential E GSH , is an accepted measure for redox conditions in a given cell compartment. In the endoplasmic reticulum (ER), E GSH is less reducing than elsewhere in the cell. However, attempts to determine E GSH (ER) have been inconsistent and based on ineligible assumptions. Using a codon-optimized and evidently glutathione-specific glutaredoxin-coupled redox-sensitive green fluorescent protein (roGFP) variant, we determined E GSH (ER) in HeLa cells as 220864 mV (at pH 7.0). At variance with existing models, this is not oxidizing enough to maintain the known redox state of protein disulfide isomerase family enzymes. Live-cell microscopy confirmed ER hypo-oxidation upon inhibition of ER Ca 2+ import. Conversely, stressing the ER with a glycosylation inhibitor did not lead to more reducing conditions, as reported for yeast. These results, which for the first time establish the oxidative capacity of glutathione in the ER, illustrate a context-dependent interplay between ER stress and E GSH (ER). The reported development of ER-localized E GSH sensors will enable more targeted in vivo redox analyses in ERrelated disorders.

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“…1).The protein disulfide isomerase family and thiol-disulfide oxidoreductases are likely enzymes involved in cardiac myocyte disulfide bond formation. Interestingly, cardiac expression of the protein disulfide isomerase transcript has been reported to be upregulated in cardiac disease (37 ). Cellular experiments further suggest a direct cardioprotective effect of this regulation.…”

Section: Reviewsmentioning

confidence: 97%

B-Type Natriuretic Peptide: From Posttranslational Processing to Clinical Measurement

Goetze

2012

Clinical Chemistry

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BACKGROUND Plasma cardiac natriuretic peptides and peptide fragments from their molecular precursors are markers of heart disease. Clinical studies have defined the current diagnostic utility of these markers, whereas biochemical elucidation of peptide structure and posttranslational processing has revealed new plasma peptide forms of potential clinical use. CONTENT Natriuretic propeptide structures undergo variable degrees of endo- and exoproteolytic cleavages as well as amino acid modifications, which leave the plasma phase of the peptides highly heterogeneous and dependent on cardiac pathophysiology and capacity. An ongoing characterization of the molecular heterogeneity may not only help us to appreciate the biosynthetic capacity of the endocrine heart but may also lead to the discovery of new and more disease-specific targets for future molecular diagnosis. SUMMARY Peptides derived from pro–atrial natriuretic peptide and pro–B-type natriuretic peptide are useful plasma markers in heart failure. New data have defined cardiac myocytes as competent endocrine cells in posttranslational processing and cellular secretion.

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Identification of Protein Disulfide Isomerase as a Cardiomyocyte Survival Factor in Ischemic Cardiomyopathy

Abstract: These results suggest that PDI promotes survival after ischemic damage and that zinc-superoxide dismutase is one of the PDI molecular targets. Pharmacological modulation of this pathway might prove useful for future prevention and treatment of HF.

Cited by 103 publications

References 24 publications

Aldehyde Dehydrogenase-2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

Aldehyde Dehydrogenase-2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

Endoplasmic reticulum: Reduced and oxidized glutathione revisited

B-Type Natriuretic Peptide: From Posttranslational Processing to Clinical Measurement

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