Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II–Infused Rats

Ishizaka, Nobukazu; Saito, Kan; Mori, Ichiro; Matsuzaki, Gen; Ohno, Minoru; Nagai, Ryozo

doi:10.1161/01.atv.0000181763.57495.2b

Cited by 55 publications

(39 citation statements)

References 50 publications

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“…This can occur through enhancement of oxidative stress by iron-catalyzed hydroxyl radical formation, via Fenton chemistry, and subsequent lipid peroxidation. 31 The current work is the first demonstration that Ang II treatment can cause iron accumulation in AAA in an apoEdeficient mouse model and that AR9276 can reduce this iron accumulation.…”

Section: Discussionmentioning

confidence: 76%

“…One interesting finding in the present study is iron accumulation in the intima and adventitia of Ang II-induced AAA. Iron accumulation, which has been reported in humans 30 and in an Ang II-treated rat model, 31 may exacerbate Ang II-induced vascular damage. This can occur through enhancement of oxidative stress by iron-catalyzed hydroxyl radical formation, via Fenton chemistry, and subsequent lipid peroxidation.…”

Section: Discussionmentioning

confidence: 87%

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Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia

Zhang

Vincelette

Cheng

et al. 2009

ATVB

106

107

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Objective-Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects. Methods and Results-Six-month-old apolipoprotein E-deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1␣, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall. Key Words: epoxyeicosatrienoic acids Ⅲ soluble epoxide hydrolase Ⅲ dyslipidemia Ⅲ atherosclerosis Ⅲ abdominal aorta aneurysm Ⅲ inflammatory markers A rachidonic acid can be metabolized by 3 major oxidative pathways: cyclooxygenase (COX) forming prostaglandins; lipoxygenase (LOX) forming hydroxyeicosatetraenoic acids (HETEs) and leukotrienes; and cytochrome P-450 monooxygenase forming epoxides and HETEs. 1 The COX and LOX pathways have been extensively studied, and their eicosanoid products have been shown to play important roles in a variety of biological processes such as inflammation, cell proliferation, and intracellular signaling. In contrast, less is known about the "third pathway" of arachidonic acid metabolism. Recently, epoxyeicosatrienoic acids (EETs), the cytochrome P450 metabolites of arachidonic acid, have received increasing attention for multiple beneficial biological functions, including vasodilation, antiinflammation, and inhibition of proliferation and migration of vascular smooth muscle cells. 1,2 Based on these properties, it has been postulated that EETs may exert therapeutic benefits in inflammatory vascular diseases, such as atherosclerosis. 2,3 Soluble epoxide hydrolase (s-EH) converts EETs into their corresponding dihydroxyeicosatrienoic acids (DHETs), which are generally thought to have reduced biological activity relative to EETs, and hydration of the EETs by s-EH is a dominant mechanism whereby their activity can be reduced. 4 Thus, inhibition of s-EH could be a promising therapeutic target for amplifying the beneficial effects of EETs. 4 Indeed, s-EH inhibitors have been demonstrated to lower blood pressure in hypertension, 5,6 decrease hypertension-induced renal damage 7 and cerebral ischemia injury, 8 attenuate vascular smooth muscle cell proliferation, 9 and reduce tissue...

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 87%

Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia

Zhang

Vincelette

Cheng

et al. 2009

ATVB

106

107

View full text Add to dashboard Cite

show abstract

“…The following respective sense and antisense primers were used: 5′-AAGTCCTGCTGAGCGAAGAT-3′ and 5′-TGGTCCCTA AATGCAGTCTG-3′ for IRE(+)DMT1; 5′-TCTACCTCC TGAACACCGTG-3′ and 5′-CGTTAGCTTTACCCGACT CC-3′ for IRE(−)DMT1; 5′-CCAGATTATGACATTCGGT-3′ and 5′-TTGGCTCAGTATCTTTAGGT-3′ for FPN; and 5′-GGCAACAGACGAGACAGACT-3′ and 5′-ATGCAA CAGAGACCACAGGA-3′ for hepc. The primers used for TfR and GAPDH have been described previously (19). The mRNA expression of these genes was normalized to GAPDH mRNA expression and is presented here as the percentage of the values from the aortas of untreated animals.…”

Section: Rna Extraction Northern Blot Analysis and Real Time Rt-pcrmentioning

confidence: 99%

Angiotensin II-Induced Regulation of the Expression and Localization of Iron Metabolism-Related Genes in the Rat Kidney

et al. 2007

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“…Alterations of the miR-122/CCL2 pathway may account for the inability of Vit.E to alleviate IO-induced hepatic inflammation because Vit.E intervention had no effect on the miR-122/CCL2 pathway. It has been reported that the intracellular iron content may affect the CCL2 expression in neuroblastoma and astrocytoma cell lines [24], rat aorta [25] and heart tissues [26], and mice cardiovascular systems [27]. Otogawa et al used an acute liver injury model that is induced by thioacetamide [28].…”

Section: Discussionmentioning

confidence: 99%

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

Tang¹,

Jia²,

Niu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Iron overload (IO) is accompanied by hepatic inflammation. The chemokine (C-C motif) ligand 2 (CCL2) mediates inflammation, and its overexpression is associated with IO. However, whether IO results in CCL2 overexpression in the liver and the underlying mechanisms are unclear. Methods: We subjected mice to IO by administering intraperitoneal injections of dextran-iron or by feeding mice a 3% dextran-iron diet to observe the effects of IO on miR-122/CCL2 expression through real-time qPCR and Western blot analysis. We also used indicators, including the expression of the inflammatory cytokine, the inflammation score based on H&E staining and the serum content of ALT and AST to evaluate the effects of IO on hepatic inflammation. Meanwhile, we observed the effects of vitamin E on IO-induced hepatic inflammation. In cells, we used 100 µΜ FeSO₄ or 30 µΜ Holo-Tf to produce IO and observed the roles of miR-122 in regulating CCL2 expression by using miR-122 mimics or inhibitors to overexpress or inhibit miR-122. Then, we used a dual-luciferase reporter assay to prove that miR-122 regulates CCL2 expression through direct binding to its complementary sequence in the CCL2 mRNA 3’UTR. Results: IO induces the downregulation of miR-122 and the upregulation of CCL2, as well as inflammatory responses both in vitro and in vivo. Although IO-induced oxidative stress is eliminated by the antioxidant vitamin E, IO-induced hepatic inflammation still exists, which probably can be explained by the fact that vitamin E has no effects on the miR-122/CCL2 pathway. In in vitro experiments, the overexpression and inhibition of miR-122 significantly reduced and increased CCL2 expression, respectively. The dual-luciferase reporter assay indicates that miR-122 binds CCL2 mRNA 3’UTR. Conclusion: We propose the roles of miR-122/CCL2 in IO-induced hepatic inflammation. Our studies should provide a new clue for developing clinical strategies for patients with IO.

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Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II–Infused Rats

Cited by 55 publications

References 50 publications

Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia

Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia

Angiotensin II-Induced Regulation of the Expression and Localization of Iron Metabolism-Related Genes in the Rat Kidney

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

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