Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction

Abueid, Leyla; Uslu, Ünal; Cumbul, Alev; Öğünç, Ayliz Velioğlu; Ercan, Feríha; Ali̇can, İnci̇

doi:10.14744/anatoljcardiol.2016.7248

Cited by 10 publications

(9 citation statements)

References 36 publications

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“…Recently, a study reported the cardioprotective effects of zileuton, namely, good protective effects against H 2 O 2 -induced oxidative stress and cell damage in both cardiac myogenic H9c2 cells, and neonatal rat cardiomyocytes (NRCMs) were found [8]. Zileuton has been reported to protect against myocardial infarction injury in a rat model [9]. Zileuton was also found to inhibit the development of pulmonary hypertension in rats [10].…”

Section: Introductionmentioning

confidence: 99%

The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPARα

Deng

Yang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Zileuton has been demonstrated to be an anti-inflammatory agent due to its well-known ability to inhibit 5-lipoxygenase (5-LOX). However, the effects of zileuton on cardiac remodeling are unclear. In this study, the effects of zileuton on pressure overload-induced cardiac remodeling were investigated and the possible mechanisms were examined. Aortic banding was performed on mice to induce a cardiac remodeling model, and the mice were then treated with zileuton 1 week after surgery. We also stimulated neonatal rat cardiomyocytes with phenylephrine (PE) and then treated them with zileuton. Our data indicated that zileuton protected mice from pressure overload-induced cardiac hypertrophy, fibrosis, and oxidative stress. Zileuton also attenuated PE-induced cardiomyocyte hypertrophy in a time- and dose-dependent manner. Mechanistically, we found that zileuton activated PPARα, but not PPARγ or PPARθ, thus inducing Keap and NRF2 activation. This was confirmed with the PPARα inhibitor GW7647 and NRF2 siRNA, which abolished the protective effects of zileuton on cardiomyocytes. Moreover, PPARα knockdown abolished the anticardiac remodeling effects of zileuton in vivo. Taken together, our data indicate that zileuton protects against pressure overload-induced cardiac remodeling by activating PPARα/NRF2 signaling.

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Section: Introductionmentioning

confidence: 99%

The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPARα

Deng

Yang

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Earlier studies showed that Zileuton reduces apoptosis and relieves inflammatory events in various models [ 6 , 26 , 27 ]. Consistent with those findings, we observed that Zileuton suppressed pro-apoptotic transcriptional changes (increased expression of BAX and decreased expression of Bcl2) induced by SAH as well as the corresponding increase in the incidence of apoptotic (TUNEL-positive) cells.…”

Section: Discussionmentioning

confidence: 99%

5-Lipoxygenase inhibition reduces inflammation and neuronal apoptosis via AKT signaling after subarachnoid hemorrhage in rats

Liu

Zhang

et al. 2021

Aging

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Early brain injury (EBI) is a major contributor to the high mortality and morbidity after subarachnoid hemorrhage (SAH). Inflammatory responses and neuronal apoptosis are important causes of EBI. Because 5- lipoxygenase (5-LOX) is known to be involved various central nervous system diseases, we investigated the effects of 5-LOX inhibition during EBI after SAH. Zileuton and LY294002 were used to inhibit expression of 5-LOX and Akt, respectively. We found that 5-LOX expression was significantly increased in the cytoplasm of cortical neurons after SAH and was accompanied by upregulated expression of the inflammatory factors LTB4, TNF-α, IL-1β and IL-6; upregulation of the pro-apoptotic factor Bax; downregulation of the anti-apoptotic factor Bcl-2; and an increased apoptosis rate. Gastric Zileuton administration significantly suppressed all of those effects and improved neurological function. Zileuton also upregulated activated (phosphorylated) AKT levels, and these beneficial effects of Zileuton were abolished by intracerebroventricular infusion of the PI3K inhibitor LY294002. Taken together, these findings indicate that 5-LOX mediates pro-inflammatory and pro-apoptotic effects that contribute to EBI after SAH and that those effects are suppressed by activation of PI3K/Akt signaling. This suggests targeting 5-LOX may be an effective approach to treating EBI after SAH.

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“…An in situ cell death detection peroxidase (POD) kit (Roche Diagnostics, Mannheim, Germany) was used for the TUNEL technique and the sections were stained according to the manufacturer's protocol. In each sampling frame, a counting area was designated without bias and the apoptotic index was calculated by dividing the apoptotic (TUNEL-positive) RGC number by the total RGC number [19]. TUNEL-positive RGCs were counted by the same investigator (UU) blinded to the group assignment.…”

Section: Tunel Assay and Apoptotic Indexmentioning

confidence: 99%

Possible antiapoptotic and neuroprotective effects of magnesium sulphate on retina in a preterm hypoxic-ischemic rat model

İmamoğlu¹,

İmamoğlu²,

Erdenöz³

et al. 2021

Turk J Med Sci

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Background/aim: The effects of systemic magnesium sulfate (MgSO 4 ) on retina in preterm hypoxic-ischemic (HI) rat model are not known. Our aim was to investigate the effects of MgSO 4 on retinal ganglion cell (RGC) count, retinal ganglion cell (RGC) apoptotic index, retinal vascular endothelial growth factor receptor-2 (VEGFR-2), and glial fibrillary acidic protein (GFAP) expressions in preterm HI rat model. Materials and methods:Fifteen, postnatal day (PND) 7 rat pups were divided into 3 groups: 1. Sham-operated group, 2. HI group, and 3. MgSO 4 -treated HI group. The second and third groups underwent ischemia followed by exposure to hypoxia for 2 h (Vannucci model). The first and second groups received intraperitoneal saline and the third group received intraperitoneal MgSO 4 . On PND 10, eyes of the pups were evaluated for RGC count, apoptotic index, VEGFR-2, and GFAP expressions. Results:In both HI and MgSO 4 -treated HI group, the mean total RGC counts were found to be significantly decreased. However, the mean total RGC count in the MgSO 4 -treated HI group was significantly higher than that of the HI group. The mean apoptotic index was found to be significantly increased in the HI group. Retinal VEGFR-2 and GFAP expressions were found to be significantly higher in the HI group.Conclusions: Magnesium sulfate preconditioning and treatment in preterm HI rat model might diminish apoptosis, relatively preserve RGCs, and reduce retinal VEGFR-2 and GFAP expressions.

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Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction

Cited by 10 publications

References 36 publications

The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPARα

The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPARα

5-Lipoxygenase inhibition reduces inflammation and neuronal apoptosis via AKT signaling after subarachnoid hemorrhage in rats

Possible antiapoptotic and neuroprotective effects of magnesium sulphate on retina in a preterm hypoxic-ischemic rat model

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