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Iron chelation and a free radical scavenger suppress angiotensin II-induced upregulation of TGF-1 in the heart

Departments of ¹Cardiovascular Medicine and ²Metabolic Disease and ³Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, and ⁴Department of Pathology, Wakayama Medical College, Tokyo, Japan

Submitted 8 July 2004 ; accepted in final form 16 November 2004

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-1 (TGF-1). Angiotensin II infusion for 7 days caused a robust increase in TGF-1 mRNA expression in vascular smooth muscle cells, myofibroblast-like cells, and migrated monocytes/macrophages. T-0970 and deferoxamine suppressed the upregulation of TGF-1 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-1 and monocyte chemoattractant protein-1.

fibrosis; iron chelator; oxidative stress; aldosterone

This article has been cited by other articles:

				N. Ishizaka, K. Saito, I. Mori, G. Matsuzaki, M. Ohno, and R. Nagai Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II-Infused Rats Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2282 - 2288. [Abstract] [Full Text] [PDF]