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¹ Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
² PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan
³ Department of Diabetes, Metabolism and Endocrinology and ⁴ Department of Cardiology, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan
⁵ Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
⁶ Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan

CORRESPONDENCE Issei Komuro: komuro-tky{at}umin.ac.jp

To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.

Abbreviations used: cDNA, complementary DNA; FS, fractional shortening; HETE, hydroxy-eicosatetraenoic acids; LOX, lipoxygenase; LVDd, left ventricular diastolic dimension; MCP-1, monocyte chemoattractant protein 1; mRNA, messenger RNA; TAC, transverse aortic constriction.

© 2009 Kayama et al.
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