Iron chelation and a free radical scavenger suppress angiotensin II-induced upregulation of TGF-β1 in the heart

Saito, Kan; Ishizaka, Nobukazu; Aizawa, Toru; Sata, Masataka; Iso-O, Naoyuki; Noiri, Eisei; Mori, Ichiro; Ohno, Minoru; Nagai, Ryozo

doi:10.1152/ajpheart.00679.2004

Cited by 34 publications

(28 citation statements)

References 38 publications

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“…Recent studies also suggested that iron and/or iron-mediated increase in the extent of oxidative stress play a role in the fibrotic changes not only in the liver 16,33 but also in other organs such as heart. 34,35 Our data may suggest the possibility that iron may also have a role in the vascular remodeling in vivo in certain diseased conditions, such as increased circulating Ang II.…”

Section: Discussionmentioning

confidence: 83%

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

Ishizaka

Saito

Mori

et al. 2005

ATVB

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Objective-We have investigated whether long-term administration of angiotensin (Ang) II causes ferritin induction and iron accumulation in the rat aorta, and their possible relation to regulatory effects on gene expression and vascular function in Ang II-infused animals. Methods and Results-Sprague-Dawley rats were given Ang II for 7 days via subcutaneously implanted osmotic minipumps. Ang II infusion caused a Ͼ20-fold increase in ferritin protein expression over control values. Immunohistochemistry showed that Ang II infusion markedly increased the ferritin expression in the aortic endothelial and adventitial cells, with some of the latter being identified as monocytes/macrophages. Prussian blue staining showed that stainable iron was observed in the adventitial layer of aorta from Ang II-infused animals, but not in the endothelial layer. Chelation of iron suppressed aortic induction of ferritin and also the oxidative stress markers, heme oxygenase-1 and 4-hydroxynonenal-modified protein adducts. In addition, iron chelation attenuated Ang II-induced impairment of aortic relaxations in response to acetylcholine and sodium nitroprusside and suppressed upregulation of mRNA levels of monocyte chemoattractant protein-1. Iron chelation also partially attenuated the medial thickening and perivascular fibrosis induced by Ang II infusion for 4 weeks. Conclusion-Ang

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Section: Discussionmentioning

confidence: 83%

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

Ishizaka

Saito

Mori

et al. 2005

ATVB

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“…Ishizaka et al showed that DFO treatment prevented cardiovascular fibrosis induced by AngII by inhibiting oxidative stress and macrophage infiltration [13], [14]. They also reported that iron chelation suppressed AngII-induced TGF-β1 upregulation in the kidney [19] and heart [37]. A low-iron diet attenuated the expression of TGF-β1 and the upregulation of collagen III in a CKD rat model [21].…”

Section: Discussionmentioning

confidence: 99%

Iron Chelation by Deferoxamine Prevents Renal Interstitial Fibrosis in Mice with Unilateral Ureteral Obstruction

et al. 2014

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Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22phox expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses.

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“…Zhao et al showed that AngII induced Nox2 and TGF-β expression, accompanied by extensive perivascular and interstitial fibrosis in both ventricles of rat heart; the antioxidants apocynin and tempol, on the other hand, blocked AngII-induced Nox2 and TGF-β expression [49]. The iron chelator deforoxamine and the free radical scavenger T-0970 have also been shown to suppress AngII-induced TGF-β expression in rat heart [134]. Single-walled carbon nanotubes induced TGF-β expression, which was significantly attenuated in Nox2 null mice [135].…”

Section: Ros and Tgf-β’s Fibrogenesismentioning

confidence: 99%

Oxidative stress and glutathione in TGF-β-mediated fibrogenesis

Liu

Pravia

2010

Free Radical Biology and Medicine

399

338

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Transforming growth factor beta (TGF-β) is the most potent and ubiquitous profibrogenic cytokine and its expression is increased in almost all the fibrotic diseases and in experimental fibrosis models. TGF-β increases ROS production and decreases the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, in various types of cells, which mediates many of TGF-β’s fibrogenic effects. A decreased GSH concentration is also observed in human fibrotic diseases and in experimental fibrosis models. Although the biological significance of GSH depletion in the development of fibrosis remains obscure, GSH and N-acetylcysteine (NAC), a precursor of GSH, have been used in clinics for the treatment of fibrotic diseases. This review summarizes recent findings in the field to address the potential mechanism whereby oxidative stress mediates TGF-β’s fibrogenesis and the potential therapeutic values of antioxidant treatment in fibrotic diseases.

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Iron chelation and a free radical scavenger suppress angiotensin II-induced upregulation of TGF-β1 in the heart

Cited by 34 publications

References 38 publications

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

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

Iron Chelation by Deferoxamine Prevents Renal Interstitial Fibrosis in Mice with Unilateral Ureteral Obstruction

Oxidative stress and glutathione in TGF-β-mediated fibrogenesis

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