Cardiac 12/15 lipoxygenase-induced inflammation is involved in heart failure.
Cardiac 12/15 lipoxygenase-induced inflammation is involved in heart failure.
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DOI：
10.1084/jem.20082596
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发表时间：
2009-07-06
期刊：
影响因子：
--
通讯作者：
Komuro I
中科院分区：
文献类型：
--
作者：
Kayama Y;Minamino T;Toko H;Sakamoto M;Shimizu I;Takahashi H;Okada S;Tateno K;Moriya J;Yokoyama M;Nojima A;Yoshimura M;Egashira K;Aburatani H;Komuro I
为了确定治疗心力衰竭的新靶点，我们检查了衰竭心脏中的基因表达。在所分析的基因中，编码蛋白12/15脂氧合酶（LOX）的Alox15在心力衰竭中显著上调。为了确定12/15-LOX表达增加是否会导致心力衰竭，我们在心肌细胞中建立了过表达12/15-LOX的转基因小鼠。超声心动图显示Alox15转基因小鼠出现收缩功能障碍。Alox15转基因小鼠的心脏纤维化随着年龄的增长而增加，并与巨噬细胞的浸润有关。与这些观察结果一致，与野生型小鼠相比，Alox15转基因小鼠心脏单核细胞化学引诱蛋白1 （MCP-1）的表达上调。12/15-LOX的主要代谢物- 12-羟基二十碳四烯酸可以增加MCP-1在心脏成纤维细胞和内皮细胞中的表达，但在心肌细胞中没有。在Alox15转基因小鼠中，抑制MCP-1可减少巨噬细胞向心肌的浸润，防止收缩功能障碍和心脏纤维化。同样，12/15-LOX的破坏可显著降低心脏MCP-1表达和巨噬细胞浸润，从而改善慢性压力过载引起的收缩功能障碍。我们的研究结果表明，心脏12/15-LOX参与心力衰竭的发展，抑制12/15-LOX可能是治疗心力衰竭的一种新方法。
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.
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DOI：
10.1161/01.atv.0000217909.09198.d6
发表时间：
2006-06-01
影响因子：
8.7
作者：
Bolick, David T.;Srinivasan, Suseela;Hedrick, Catherine C.
通讯作者：
Hedrick, Catherine C.
DOI：
10.1161/01.atv.0000186181.19909.a6
发表时间：
2005-11-01
影响因子：
8.7
作者：
Bolick, DT;Orr, AW;Hedrick, CC
通讯作者：
Hedrick, CC
影响因子：
37.8
作者：
Hayashidani, S;Tsutsui, H;Takeshita, A
通讯作者：
Takeshita, A
病毒载体介导的血管平滑肌细胞中12/15-脂氧合酶过度表达增强炎症基因表达和迁移
影响因子：
1.7
作者：
Dwarakanath, Roopashree S.;Sahar, Saurabh;Reddy, Marpadga A.
通讯作者：
Reddy, Marpadga A.
影响因子：
7.7
作者：
McDuffie, Marcia;Maybee, Nelly A.;Nadler, Jerry L.
通讯作者：
Nadler, Jerry L.