Cardiac 12/15 lipoxygenase-induced inflammation is involved in heart failure

Yosuke Kayama, Tohru Minamino, Haruhiro Toko, Masaya Sakamoto, Ippei Shimizu, Hidehisa Takahashi, Sho Okada, Kaoru Tateno, Junji Moriya, Masataka Yokoyama, Aika Nojima, Michihiro Yoshimura, Kensuke Egashira, Hiroyuki Aburatani, Issei Komuro

    Research output: Contribution to journalArticlepeer-review

    80 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)1565-1574
    Number of pages10
    JournalJournal of Experimental Medicine
    Volume206
    Issue number7
    DOIs
    Publication statusPublished - Jul 6 2009

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology

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