Role of thioredoxin-1 in ischemic preconditioning, postconditioning and aged ischemic hearts

D'Annunzio, Verónica; Pérez, Virginia; Boveris, Alberto; Gelpi, Ricardo J.; Poderoso, Juan José

doi:10.1016/j.phrs.2016.03.009

Cited by 23 publications

(14 citation statements)

References 95 publications

(133 reference statements)

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“…Previous studies demonstrated that the anti-oxidative proteins SOD (superoxide dismutase) and/or thioredoxin are decreased in myocardial ischemia/reperfusion injury or other oxidation stress1819. Similarly, in isolated hearts with ischemia/reperfusion injury, we also found (Fig.…”

Section: Resultssupporting

confidence: 83%

Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury

Liu

Yang

et al. 2016

Sci Rep

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The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.

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Section: Resultssupporting

confidence: 83%

Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury

Liu

Yang

et al. 2016

Sci Rep

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“…In Tg-Trx1 mice, the infarct size following I/R was reduced compared to in WT mice, but postconditioning did not show an additive effect. In contrast, in Tg-DN-Trx1, the protective effect of postconditioning was not observed [63, 64]. Furthermore, in young mice, ischemic postconditioning conferred a protective phenotype after I/R by preventing Trx1 degradation and, thus, increasing Akt and GSK-3β phosphorylation.…”

Section: Role Of Trx1 In the Heart In Vivomentioning

confidence: 99%

“…Furthermore, in young mice, ischemic postconditioning conferred a protective phenotype after I/R by preventing Trx1 degradation and, thus, increasing Akt and GSK-3β phosphorylation. However, the postconditioning effect was abolished in middle-aged and older mice, as Trx1 was degraded rapidly [64, 65]. This suggests that Trx1 plays an important role in mediating the cardioprotection afforded by ischemic postconditioning.…”

Section: Role Of Trx1 In the Heart In Vivomentioning

confidence: 99%

Modulation of signaling mechanisms in the heart by thioredoxin 1

Nagarajan

Oka

Sadoshima

2017

Free Radical Biology and Medicine

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Myocardial ischemia/reperfusion and heart failure are the major cardiac conditions in which an imbalance between oxidative stress and anti-oxidant mechanisms is observed. The myocardium has endogenous reducing mechanisms, including the thioredoxin (Trx) and glutathione systems, that act to scavenge reactive oxygen species (ROS) and reduce oxidized proteins. The Trx system consists of Trx, Trx reductase (TrxR), and an electron donor, NADPH, where Trx is maintained in a reduced state in the presence of TrxR and NADPH. Trx1, a major isoform of Trx, is abundantly expressed in the heart and exerts its oxidoreductase activity through conserved Cys32 and Cys35, reducing oxidized proteins through thiol disulfide exchange reactions. In this review, we will focus on molecular targets of Trx1 in the heart, including transcription factors, microRNAs, histone deactylases, and protein kinases. We will then discuss how Trx1 regulates the functions of its targets, thereby affecting the extent of myocardial injury caused by myocardial ischemia/reperfusion and the progression of heart failure.

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“…Thus, Trx is believed to be a potent scavenger of ROS. Additionally, Trx has multiple functions, including antioxidant ( D’Annunzio et al ., 2016 ), anti-inflammatory ( Chen et al ., 2016 ), and anti-apoptotic ( Kamimoto et al ., 2010 ) activities. The administration of recombinant human Trx (rhTrx) was recently shown to attenuate several diseases associated with oxidant-induced apoptosis, including ischemia/reperfusion-induced myocardial damage ( Tao et al ., 2006 ), transient focal cerebral ischemia ( Wang et al ., 2015 ) and ethanol-induced liver injury ( Cohen et al ., 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Recombinant Human Thioredoxin-1 Protects Macrophages from Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation and Cell Apoptosis

Zhang

Liu

Lin

et al. 2018

Biomolecules & Therapeutics

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Oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and apoptosis play critical roles in the pathogenesis of atherosclerosis. Thioredoxin-1 (Trx) is an antioxidant that potently protects various cells from oxidative stress-induced cell death. However, the protective effect of Trx on ox-LDL-induced macrophage foam cell formation and apoptosis has not been studied. This study aims to investigate the effect of recombinant human Trx (rhTrx) on ox-LDL-stimulated RAW264.7 macrophages and elucidate the possible mechanisms. RhTrx significantly inhibited ox-LDL-induced cholesterol accumulation and apoptosis in RAW264.7 macrophages. RhTrx also suppressed the ox-LDL-induced overproduction of lectin-like oxidized LDL receptor (LOX-1), Bax and activated caspase-3, but it increased the expression of Bcl-2. In addition, rhTrx markedly inhibited the ox-LDL-induced production of intracellular reactive oxygen species (ROS) and phosphorylation of p38 mitogen-activated protein kinases (MAPK). Furthermore, anisomycin (a p38 MAPK activator) abolished the protective effect of rhTrx on ox-LDL-stimulated RAW264.7 cells, and SB203580 (a p38 MAPK inhibitor) exerted a similar effect as rhTrx. Collectively, these findings indicate that rhTrx suppresses ox-LDL-stimulated foam cell formation and macrophage apoptosis by inhibiting ROS generation, p38 MAPK activation and LOX-1 expression. Therefore, we propose that rhTrx has therapeutic potential in the prevention and treatment of atherosclerosis.

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Role of thioredoxin-1 in ischemic preconditioning, postconditioning and aged ischemic hearts

Cited by 23 publications

References 95 publications

Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury

Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury

Modulation of signaling mechanisms in the heart by thioredoxin 1

Recombinant Human Thioredoxin-1 Protects Macrophages from Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation and Cell Apoptosis

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