Nox2ds-Tat, A Peptide Inhibitor of NADPH Oxidase, Exerts Cardioprotective Effects by Attenuating Reactive Oxygen Species During Ischemia/Reperfusion Injury

Chen, Qian; Devine, Issachar; Walker, Sydney; Pham, Hung; Ondrasik, Regina; Patel, Harsh; Chau, William; Parker, Crawford; Bartol, Kyle D.; Riahi, Shayan; Mittal, Ashita; Barsotti, Robert; Young, Lindon H.

doi:10.5099/aj160300208

Cited by 5 publications

(9 citation statements)

References 36 publications

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“…At the end of the experiment, the heart was crosssectioned into 2 mm sections from apex to base. The heart crosssections were subjected to 1% Triphenyltetrazolium Chloride (TTC) staining for 15 min at 37 °C to determine infarct size as previously described [20,27,28].…”

Section: Myocardial I/r Proceduresmentioning

confidence: 99%

“…The microsensors were connected to a free radical analyzer (Apollo 4000, WPI, Inc., Sarasota, FL). This arrangement allowed for real-time measurements of H 2 O 2 or NO release as previously described [18,20,29]. One limb was subjected to I/R via clamping of the femoral artery and vein for 30 min followed by reperfusion for 45 min.…”

Section: Hindlimb I/r Proceduresmentioning

confidence: 99%

“…It is well known that when BH 2 is increased during reperfusion, eNOS becomes uncoupled and produces SO instead of NO [17][18][19]. Thus, reducing mitochondrial-derived ROS would also reduce additional ROS generated by uncoupled eNOS during reperfusion [18,20]. Although both MitoQ and SS-31 concentrate their antioxidant properties within mitochondria, their mechanisms targeting the mitochondria differ.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial-Targeted Antioxidants Given at Reperfusion Protect Cardiac and Hindlimb Muscles against Ischemia/Reperfusion Injury

2019

J Cardiobiol

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Background and purpose:The principal cause of cardiomyocyte dysfunction and necrosis resulting from Ischemia/Reperfusion (I/R) injury is the production and release of Reactive Oxygen Species (ROS) from damaged mitochondria. Mitochondrial ROS-mediated oxidation of cellular proteins and lipids disrupts both cellular metabolism and organelle integrity, leading to depletion of ATP stores and an increase in intracellular calcium (Ca 2+ ) levels. Thus, attenuation of I/R-induced ROS production has been a therapeutic strategy to salvage damaged cardiomyocytes and thereby limit cardiac functional impairment and infarct size [1]. Previous studies have tested the effectiveness of mitochondrial-targeted antioxidants. Mitoquinone (MitoQ) was effective in reducing I/R injury when given only prior to prolonged ischemia, while Szeto-Schiller (SS)-31 was effective when given either prior to ischemia or at the beginning of reperfusion. This study was undertaken to determine whether these agents are effective in limiting myocardial and hindlimb I/R injury when given during the first 5min of reperfusion only, and thereby support the premise that mitochondrial damage underlies reperfusion-induced cell death during the initial minutes of reperfusion.Experimental approach: Male Sprague-Dawley rats (275-325 g) were randomized into myocardial or hindlimb I/R groups. Isolated, retrogradely perfused hearts were subjected to global I(30 min)/R(45 min). Hearts were treated with MitoQ (1-20 µM), SS-31 (10-100 µM), or plasma (control) added to the perfusate at the onset of reperfusion and was assessed for cardiac function and infarct size. In the hindlimb experiments, either hydrogen peroxide (H 2 O 2 ) or Nitric Oxide (NO) sensors were placed randomly in both the right and left femoral veins of the same animal. One limb was subjected to I(30 min)/R(45 min) by reversibly clamping the femoral artery/vein, while the other limb served as a sham. The animal received an intravenous (i.v.) bolus of either MitoQ (1.8 mg kg -1 ), SS-31 (2.5 mg kg -1 ), or saline (control) at the beginning of reperfusion. The difference in blood H 2 O 2 or NO between the femoral vein of ischemic and sham limbs in each animal was continuously measured to assess the effects of the drugs. Key results:In the myocardial I/R model, MitoQ and SS-31 given upon reperfusion significantly improved cardiac function and reduced infarct size compared to untreated control hearts. In the hindlimb I/R model, elevations in blood H 2 O 2 levels and reductions in blood NO, both indices of elevated ROS, were significantly attenuated by both MitoQ and SS-31 given upon reperfusion compared to saline treated control animals. Conclusion and implications:The results indicate that mitochondrial-derived ROS is a major contributor to reperfusion injury and that MitoQ and SS-31 work expeditiously to attenuate ROS in that both agents improve cardiac function and limit infarct size when administered only at the onset of reperfusion. The data suggest that MitoQ or SS-31 would be an effective adjuvant...

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Section: Myocardial I/r Proceduresmentioning

confidence: 99%

Section: Hindlimb I/r Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial-Targeted Antioxidants Given at Reperfusion Protect Cardiac and Hindlimb Muscles against Ischemia/Reperfusion Injury

2019

J Cardiobiol

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“…However, good results have been obtained in the evaluation of Nox2ds-tat, which includes a portion of the chemical structure from compounds of the first generation (the tat portion), which was included to improve Nox2ds delivery into the cell. Several articles have reported that the inhibitory activity of gp91ds-tat is better in a cell-free system in comparison to cell system evaluation [ 144 ]. In addition, very limited oral bioavailability has been reported in several articles [ 145 , 146 ].…”

Section: Introductionmentioning

confidence: 99%

Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer’s Disease Murine Models

2021

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Alzheimer’s disease (AD) is one of the main human dementias around the world which is constantly increasing every year due to several factors (age, genetics, environment, etc.) and there are no prevention or treatment options to cure it. AD is characterized by memory loss associated with oxidative stress (OS) in brain cells (neurons, astrocytes, microglia, etc.). OS can be produced by amyloid beta (Aβ) protein aggregation and its interaction with metals, mitochondrial damage and alterations between antioxidants and oxidant enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase produces reactive oxygen species (ROS) and it is overexpressed in AD, producing large amounts of superoxide anions and hydrogen peroxide which damage brain cells and the vasculature. In addition, it has been reported that NADPH oxidase causes an imbalance of pH which could also influence in the amyloid beta (Aβ) production. Therefore, NADPH oxidase had been proposed as a therapeutic target in AD. However, there are no drugs for AD treatment such as an NADPH oxidase inhibitor despite great efforts made to stabilize the ROS production using antioxidant molecules. So, in this work, we will focus our attention on NADPH oxidase (NOX2 and NOX4) in AD as well as in AD models and later discuss the use of NADPH oxidase inhibitor compounds in AD.

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“…It is widely accepted that both UC and CD are caused by inflammation-related cytokine-driven mixed infiltrates in the intestinal mucosa [7] . Some proinflammatory cytokines such as TNF-α, IL-1b, IL-6, and IL-17 also play crucial roles in disease pathogenesis [8][9][10]. Inhibition of lipid peroxidation or scavenging of oxygen free radicals would a rationale for therapeutic modulation with antioxidants [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

A Novel Role of Vitamin K in Amelioration of Experimental Induced Ulcerative Colitis in Rats

Abozaid¹,

Ashour²

2020

Am. J. Biomed. Sci.

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Background:The presence of inflammatory mediators and free radicals are well-known features in the pathogenesis of ulcerative colitis (UC). Patients with ulcerative colitis often exhibit vitamin K (vit K) deficiency. Some studies have been discussed role for vit K as anti-inflammatory and antioxidant factor in other tissues, but the modulatory role of vit K supplementation by different routes in ulcerative colitis is unclear, with its antioxidant capacity and anti-inflammatory activity, vit K would be expected to reduce injury from ulcerative colitis. The aim of this study is to verify the role of vit K in the pathophysiology of intestinal inflammation using acetic acid induced ulcerative colitis model in rats. In addition, the efficiency of vit K injection in comparison to oral vit K supplementation in such condition was investigated.Methods: 24 adult male albino rats were divided to 4 main groups (n=6): group (A) control intact received saline intrarectally and take water by gavage, (B) acetic acid-induced colitis group injected with 2 ml acetic acid (4%) intra rectally and take water by gavage), (C) acetic acid-induced colitis with oral vit K (1.6 mg/kg/d) and (D) acetic acid-induced colitis injected with vit K (1.6 mg/kg/d) intraperitoneally (ip), vit K was given 24 h after induction of colitis and persisted for 8 consecutive days. Disease activity was evaluated biochemically by measuring proinflammatory cytokine levels and oxidative stress markers in colonic tissue sample, Ulcer index, severity of inflammation and histological changes were recorded after the end of the treatment regimen.Results: Acetic acid induced colitis group B showed atrophy of lining mucosa with areas of ulceration, with inflammatory cell infiltration detected by microscopic examination and evaluated by injury score index, in addition to increased levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), myeloperoxides (MPO), malondialdehyde (MDA), and decreased levels of glutathione peroxidase (GPX) and superoxide dismutase (SOD) when compared with control group A; whereas vitamin K administration in group C and D significantly suppressed TNF-α, IL-1β, IL-6 production, increased GPX and SOD and decreased the score injury index when compared to group B. Moreover, group D showed more

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Nox2ds-Tat, A Peptide Inhibitor of NADPH Oxidase, Exerts Cardioprotective Effects by Attenuating Reactive Oxygen Species During Ischemia/Reperfusion Injury

Cited by 5 publications

References 36 publications

Mitochondrial-Targeted Antioxidants Given at Reperfusion Protect Cardiac and Hindlimb Muscles against Ischemia/Reperfusion Injury

Mitochondrial-Targeted Antioxidants Given at Reperfusion Protect Cardiac and Hindlimb Muscles against Ischemia/Reperfusion Injury

Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer’s Disease Murine Models

A Novel Role of Vitamin K in Amelioration of Experimental Induced Ulcerative Colitis in Rats

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