Tsujita Kenichi, Kaikita Koichi, Hayasaki Takanori, Honda Tsuyoshi, Kobayashi Hironori, Sakashita Naomi, Suzuki Hiroshi, Kodama Tatsuhiko, Ogawa Hisao, Takeya Motohiro
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Circulation. 2007 Apr 10;115(14):1904-11. doi: 10.1161/CIRCULATIONAHA.106.671198. Epub 2007 Mar 26.
Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A-deficient (SR-A(-/-)) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction.
Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A(-/-) and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A(-/-) mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A(-/-) mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A(-/-) mice compared with WT mice. Real-time reverse transcription-polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A(-/-) mice compared with WT mice. Furthermore, SR-A(-/-) mice showed augmented expression of tumor necrosis factor-alpha and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor-alpha and decreased interleukin-10 expression in activated SR-A(-/-) macrophages.
The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor-alpha and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.
A类巨噬细胞清道夫受体（SR-A）是一种巨噬细胞特异性的多功能分子，可通过调节炎性细胞因子的活性来优化炎症反应。本研究采用SR-A基因缺陷（SR-A(-/-)）小鼠，以评估SR-A与心肌梗死后心脏重塑之间的关系。
通过结扎SR-A(-/-)和野生型（WT）雄性小鼠的左冠状动脉制作实验性心肌梗死（MI）模型。MI后4周内死亡的SR-A(-/-)小鼠数量显著多于WT小鼠（P=0.03）。重要的是，MI后1周内由心脏破裂导致的死亡在SR-A(-/-)小鼠中为31%（54只小鼠中有17只），在WT小鼠中为12%（51只小鼠中有6只）（P=0.01）。原位酶谱分析显示，与WT小鼠相比，SR-A(-/-)小鼠梗死心肌中的明胶酶活性增强。MI后第3天的实时逆转录-聚合酶链反应显示，与WT小鼠相比，SR-A(-/-)小鼠梗死心肌中基质金属蛋白酶-9 mRNA的表达显著增加。此外，MI后第3天，SR-A(-/-)小鼠梗死心肌中肿瘤坏死因子-α的表达增强，白细胞介素-10的表达减少。体外实验也表明，活化的SR-A(-/-)巨噬细胞中肿瘤坏死因子-α的表达增加，白细胞介素-10的表达减少。
目前的研究结果表明，SR-A缺乏可能导致梗死重塑受损，进而通过白细胞介素-10产生不足以及肿瘤坏死因子-α和基质金属蛋白酶-9表达增强而导致心脏破裂。SR-A可能有助于预防MI后的心脏破裂。
