Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin.
Deletion of LOX-1 Protects against Heart Failure Induced by Doxorubicin.
复制标题
DOI：
10.1371/journal.pone.0154994
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Minatoguchi S
中科院分区：
文献类型：
--
作者：
Yokoyama C;Aoyama T;Ido T;Kakino A;Shiraki T;Tanaka T;Nishigaki K;Hasegawa A;Fujita Y;Sawamura T;Minatoguchi S
氧化应激是阿霉素（DOX）诱导心肌病的主要因素之一。血凝素样氧化低密度脂蛋白（oxLDL）受体-1（LOX-1）在缺血再灌注后心脏重构和氧化应激中起重要调节作用。因此，我们研究LOX-1是否有助于DOX诱导的心肌病的发病机制。通过将DOX单次腹膜内注射到野生型（WT）小鼠和LOX-1敲除（KO）小鼠中诱导心肌病。超声心动图和基于导管的血流动力学评估明显显示，DOX给药后，LOX-1 KO小鼠的左心室（LV）缩短分数（FS）和腔大小与WT小鼠相比有所保留。DOX给药后，LOX-1 KO小鼠中肿瘤坏死因子α（TNF-α）和白细胞介素-1 β（IL-1 β）的产生低于WT小鼠。Western blotting分析也显示DOX处理的LOX-1 KO小鼠中核因子κB（NF-κB）和p38丝裂原活化蛋白激酶（MAPK）的活化低于DOX处理的WT小鼠。事实上，与接受DOX治疗的WT小鼠相比，接受DOX治疗的LOX-1 KO小鼠中LOX-1和血管细胞粘附分子-1（VCAM-1）的NF-κ B依赖性基因表达受到抑制。因此，组织学分析显示与WT小鼠相比，LOX-1 KO小鼠中白细胞浸润和心脏纤维化减弱。同时，在用DOX给药处理的WT小鼠中细胞外信号调节激酶MAPK（ERK）失活和肌节蛋白和相关转录因子加塔-4的表达降低在用DOX给药处理的LOX-1 KO小鼠和用媒介物处理的WT和LOX-1 KO小鼠中未观察到。DOX处理后，WT小鼠中肌测量蛋白表达的减少导致心肌细胞直径小于LOX-1 KO小鼠。LOX-1在心肌细胞中的表达明显高于内皮细胞、成纤维细胞和炎性细胞。与用载体处理的那些相比，用DOX处理的内皮细胞、成纤维细胞和炎性细胞未显示LOX-1表达升高。然而，用DOX处理的心肌细胞显示LOX-1的表达比用载体处理的心肌细胞多得多。免疫组织化学研究还显示，LOX-1表达强烈升高，在心肌细胞中的小鼠心脏组织中的DOX在体内治疗。我们的结论是，LOX-1在心肌细胞中起着最重要的作用，在病理的阿霉素诱导的心肌病。LOX-1缺失改变了LOX-1相关的信号通路，这导致DOX治疗后心脏功能、心肌炎症、纤维化和退行性变化的改善。
Oxidative stress is one of the major factors in doxorubicin (DOX)-induced cardiomyopathy. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) plays an important role to regulate cardiac remodeling and oxidative stress after ischemia-reperfusion. Therefore, we examined whether or not LOX-1 contributes to the pathogenesis of DOX-induced cardiomyopathy. Cardiomyopathy was induced by a single intraperitoneal injection of DOX into wild-type (WT) mice and LOX-1 knockout (KO) mice. Echocardiography and catheter-based hemodynamic assessment apparently revealed preserved left ventricular (LV) fractional shortening (FS) and cavity size of LOX-1 KO mice compared with those of WT mice after DOX administration. Less production of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) was observed in LOX-1 KO mice than WT mice after DOX administration. Western blotting analysis also showed lower activation of nuclear factor κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in LOX-1 KO mice treated with DOX than WT mice treated with DOX. In fact, NF-κB-dependent gene expressions of LOX-1 and vascular cell adhesion molecule-1 (VCAM-1) were suppressed in LOX-1 KO mice treated with DOX compared with WT mice treated with DOX. Therefore, histological analyses showed attenuation of leukocyte infiltration and cardiac fibrosis in LOX-1 KO mice compared with WT mice. Meanwhile, extracellular signal-regulated kinase MAPK (ERK) inactivation and decreased expression of sarcomeric proteins and related transcription factor GATA-4 in WT mice treated with DOX administration were not seen in LOX-1 KO mice treated with DOX administration and WT and LOX-1 KO mice treated with vehicle. Decreased expression of sarcometric proteins resulted in smaller diameters of cardiomyocytes in WT mice than in LOX-1 KO mice after DOX treatment. The expression of LOX-1 in cardiomyocytes was much more abundant than that in endothelial cells, fibroblasts and inflammatory cells. Endothelial cells, fibroblasts and inflammatory cells treated with DOX showed no elevated LOX-1 expression compared with those treated with vehicle. However, cardiomyocytes treated with DOX showed much more expression of LOX-1 than those treated with vehicle. Immunohistochemistry study also showed that LOX-1 expression was strongly elevated in cardiomyocytes in the heart tissue of mice treated with DOX in vivo. We conclude that LOX-1 in cardiomyocytes plays the most important roles in the pathology of DOX-induced cardiomyopathy. LOX-1 deletion altered the LOX-1-related signaling pathway, which led to improvements in cardiac function, myocardial inflammation, fibrosis and degenerative changes after DOX treatment.