Cardiac 12/15 lipoxygenase-induced inflammation is involved in heart failure.
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.
Kayama
Yosuke
Y
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.
Minamino
Tohru
T
Toko
Haruhiro
H
Sakamoto
Masaya
M
Shimizu
Ippei
I
Takahashi
Hidehisa
H
Okada
Sho
S
Tateno
Kaoru
K
Moriya
Junji
J
Yokoyama
Masataka
M
Nojima
Aika
A
Yoshimura
Michihiro
M
Egashira
Kensuke
K
Aburatani
Hiroyuki
H
Komuro
Issei
I
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000276:immunology*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000276:immunology; D051381:Rats; D020303:Rats, Inbred Dahl; D017208:Rats, Wistar; D012982:Sodium, Dietary
C475064:12-15-lipoxygenase; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016859:Lipoxygenase Inhibitors; D012982:Sodium, Dietary; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase