Effect of inhibitors of myeloperoxidase on the development of aortic atherosclerosis in an animal model

Bekesi, Gabor; Heinle, H.; Kakucs, Réka; Pazmany, Tamas; Szombath, D; Dinya, Mariann; Tulassay, Zsolt; Fehér, János; Rácz, Kàroly; Székács, Béla; Riss, Éva; Farkas, A.; Gódor, Ferenc; Illyés, G.

doi:10.1016/j.exger.2004.12.004

Cited by 16 publications

(6 citation statements)

References 55 publications

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“…Moreover, quercetin did not induce cytotoxicity to HUVEC (Figure S1) and dietary administration of high doses of quercetin to mice was not toxic . Compared with the toxic side effects of other effective inhibitors (hydroxamic acids, hydrazides and azides), ,, the nontoxic effects and natural source for quercetin could increase their bioapplication in vivo.…”

Section: Discussionmentioning

confidence: 97%

Inhibitive Effects of Quercetin on Myeloperoxidase-Dependent Hypochlorous Acid Formation and Vascular Endothelial Injury

Sui

Tian

et al. 2018

J. Agric. Food Chem.

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Myeloperoxidase (MPO) from activated neutrophils plays important roles in multiple human inflammatory diseases by catalyzing the formation of powerful oxidant hypochlorous acid (HOCl). As a major flavonoid in the human diet, quercetin has been suggested to act as antioxidant and anti-inflammatory agent in vitro and in vivo. In this study, we showed that quercetin inhibited MPO-mediated HOCl formation (75.0 ± 6.2% for 10 μM quercetin versus 100 ± 5.2% for control group, P < 0.01) and cytotoxicity to endothelial cells in vitro, while this flavonoid was nontoxic to endothelial cell cultures ( P > 0.05, all cases). Moreover, quercetin inhibited HOCl generation by stimulated neutrophils (a rich source of MPO) and protected endothelial cells from neutrophils-induced injury. Furthermore, quercetin could inhibit HOCl-induced endothelial dysfunction such as loss of cell viability, and decrease of nitric oxide formation in endothelial cells ( P < 0.05, all cases). Consistent with these in vitro data, quercetin attenuated lipopolysaccharide-induced endothelial dysfunction and increase of MPO activity in mouse aortas, while this flavonoid could protect against HOCl-mediated endothelial dysfunction in isolated aortas ( P < 0.05). Therefore, it was proposed that quercetin attenuated endothelial injury in inflammatory vasculature via inhibition of vascular-bound MPO-mediated HOCl formation or scavenging of HOCl. These data indicate that quercetin is a nontoxic inhibitor of MPO activity and MPO/neutrophils-induced cytotoxicity in endothelial cells and may be useful for targeting MPO-dependent vascular disease and inflammation.

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Section: Discussionmentioning

confidence: 97%

Inhibitive Effects of Quercetin on Myeloperoxidase-Dependent Hypochlorous Acid Formation and Vascular Endothelial Injury

Sui

Tian

et al. 2018

J. Agric. Food Chem.

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“…While inhibition of MPO is considered a therapeutic strategy for MS this has not been evaluated in clinical trials because the current inhibitor classes exhibit toxicity and low specificity (Koelsch et al 2010, Burner et al 1999, Bekesi et al 2005). Thus we developed a new class of MPO inhibitors and recently showed that N-acetyl lysyltyrosylcysteine amide (KYC) was a potent, highly specific and non-toxic inhibitor of MPO-dependent oxidant/free radical generation (Zhang et al 2013a).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Zhang

Ray

Miller

et al. 2015

Journal of Neurochemistry

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Oxidative stress is thought to contribute to disease pathogenesis in the central nervous system (CNS) disease multiple sclerosis (MS). Myeloperoxidase (MPO), a potent peroxidase that generates toxic radicals and oxidants, is increased in the CNS during MS. However, the exact mechanism whereby MPO drives MS pathology is not known. We addressed this question by inhibiting MPO in mice with experimental autoimmune encephalomyelitis (EAE) using our non-toxic MPO inhibitor KYC. We found that therapeutic administration of KYC for five days starting at the peak of disease significantly attenuated EAE disease severity, reduced myeloid cell numbers and permeability of the blood-brain-barrier (BBB). These data indicate that inhibition of MPO by KYC restores BBB integrity thereby limiting migration of myeloid cells into the CNS that drive EAE pathogenesis. In addition, these observations indicate that KYC may be an effective therapeutic agent for the treatment of MS.

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“…It has been shown that MPO oxidizes its hydrazide group to the corresponding hydrazyl radical which forms covalent acyl adducts with the active site (Forbes et al 2012). Due to its commercial availability and low price, ABAH was widely used to evaluate the inhibition of MPO as a new strategy for treatment of inflammatory syndromes such as atherosclerosis in in vitro or animal models (Bekesi et al 2005) as well as multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) (Forghani et al 2012). In vivo experiments in animals demonstrated that ABAH can prevent the development of myeloid inflammation, demyelinating diseases such as MS (Forghani et al 2012), and blood-brain barrier (BBB) dysfunction (Üllen et al 2013).…”

Section: Irreversible Mpo Inhibitorsmentioning

confidence: 99%

“…In vivo experiments in animals demonstrated that ABAH can prevent the development of myeloid inflammation, demyelinating diseases such as MS (Forghani et al 2012), and blood-brain barrier (BBB) dysfunction (Üllen et al 2013). Moreover, ABAH has been found to be useful to avert the growth of aortic atherosclerosis (Bekesi et al 2005) and to block the formation of DNA double-strand breaks (Papież et al 2015). It has also been reported that the inhibition of MPO by ABAH in mice with ischemic stroke can increase the neurogenesis (Kim et al 2016).…”

Section: Irreversible Mpo Inhibitorsmentioning

confidence: 99%

Reactive Oxygen Species

Химия¹

2021

Handbook of Experimental Pharmacology

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Myeloperoxidase participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic

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Effect of inhibitors of myeloperoxidase on the development of aortic atherosclerosis in an animal model

Cited by 16 publications

References 55 publications

Inhibitive Effects of Quercetin on Myeloperoxidase-Dependent Hypochlorous Acid Formation and Vascular Endothelial Injury

Inhibitive Effects of Quercetin on Myeloperoxidase-Dependent Hypochlorous Acid Formation and Vascular Endothelial Injury

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Reactive Oxygen Species

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