To elucidate the molecular mechanisms of heart failure, we examined expression of 8800 genes in the heart of hypertensive heart failure model (Dahl salt-sensitive rats). DNA chip analysis revealed that 12-lipoxygenase (12-LOX) was markedly upregulated in the failing heart. 12-LOX is a key enzyme of the arachidonic cascade that metabolizes eicosanoid. Until recently, 12-LOX has been reported to play an important role in the development of atherogenesis, diabetes, and neurogenerative disease. However, the role of 12-LOX in heart failure has not been examined. To determine whether increased expression of 12-LOX causes heart failure, we established transgenic mice that overexpress 12-LOX only in cardiomyocytes. Echocardiogra-phy showed that 12-LOX transgenic mice developed systolic dysfunction from as early as 16 weeks old. Histological analysis revealed that cardiac fibrosis was increased in 12-LOX transgenic mice with advancing age, which was associated with infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (MCP-1) was upregulated in 12-LOX transgenic mice compared to those of wild-type mice. In vitro experiments demonstrated that treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12-LOX, increased MCP-1 expression in cardiac fibroblast and endothelial cells but not in cardiomyocytes. To determine the role of MCP-1 in the heart of 12LOX transgenic mice, we treated these mice with 7ND, an inhibitor of MCP-1, for 32 weeks. Chronic treatment with 7ND attenuated infiltration of macrophages into the myocardium and prevented systolic dysfunction and cardiac fibrosis in 12-LOX transgenic mice. Likewise, disruption of 12-LOX significantly reduced expression of MCP-1 and infiltration of macrophages in the heart, thereby inhibiting cardiac remodeling after myocardial infarction. Our in vitro and in vivo results suggest that cardiac 12-LOX is critically involved in the development of heart failure and that inhibition of 12-LOX will be a novel target for the treatment of this condition.
Monocyte Chemoattractant Protein-1 is Upregulated in Rats With Volume-Overload Congestive Heart Failure