title: Iron chelation and a free radical scavenger suppress angiotensin II-induced upregulation of TGF-beta1 in the heart.
abstract: Long-term administration of angiotensin II causes myocardial loss and cardiac fibrosis. We previously found iron deposition in the heart of the angiotensin II-infused rat, which may promote angiotensin II-induced cardiac damage. In the present study, we have investigated whether an iron chelator (deferoxamine) and a free radical scavenger (T-0970) affect the angiotensin II-induced upregulation of transforming growth factor-beta1 (TGF-beta1). Angiotensin II infusion for 7 days caused a robust increase in TGF-beta1 mRNA expression in vascular smooth muscle cells, myofibroblast-like cells, and migrated monocytes/macrophages. T-0970 and deferoxamine suppressed the upregulation of TGF-beta1 mRNA and reduced the extent of cardiac fibrosis in the heart of rats treated with angiotensin II. These agents blocked the angiotensin II-induced upregulation of heme oxygenase-1, a potent oxidative and cellular stress-responsive gene, but they did not significantly affect systolic blood pressure or plasma levels of aldosterone. In addition, T-0970 and deferoxamine suppressed the angiotensin II-induced upregulation of monocyte chemoattractant protein-1 in the heart. These results collectively suggest that iron and the iron-mediated generation of reactive oxygen species may contribute to angiotensin II-induced upregulation of profibrotic and proinflammatory genes, such as TGF-beta1 and monocyte chemoattractant protein-1.
authors.affiliation: Dept. of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Saito
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Ishizaka
authors.forename: Toru
authors.initials: T
authors.lastname: Aizawa
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Iso-o
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
authors.forename: Ichiro
authors.initials: I
authors.lastname: Mori
authors.forename: Minoru
authors.initials: M
authors.lastname: Ohno
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D003676:Deferoxamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D010671:Phenylurea Compounds; D011524:Protoporphyrins; D011725:Pyridines; D012333:RNA, Messenger; C406666:T 0970; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C017803:zinc protoporphyrin; D000450:Aldosterone; D005293:Ferritins; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D003676:Deferoxamine