LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation
LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation
复制标题
DOI：
10.1152/ajpheart.00382.2002
复制
发表时间：
2002-11-01
影响因子：
4.8
通讯作者：
Mehta, JL
中科院分区：
文献类型：
--
作者：
Li, DY;Williams, V;Mehta, JL
最近发现的凝集素样氧化低密度脂蛋白受体（LOX-1）介导内皮细胞损伤，促进炎症细胞粘附。本实验研究了LOX-1在心肌缺血再灌注损伤中的作用。对麻醉的Sprague-Dawley大鼠进行60分钟的左冠状动脉（LCA）结扎，然后再灌注60分钟。在I/R之前，用盐水、LOX-1阻断抗体JXT 21（10 mg/kg）或非特异性抗山羊IgG（10 mg/kg）处理大鼠。另外10只大鼠接受手术而不结扎LCA，并作为假手术对照组。LOX-1表达在缺血再灌注期间明显增加（P < 0.01）。同时，缺血再灌注区基质金属蛋白酶-1（MMP-1）和粘附分子P-选择素（P-selectin）、VCAM-1和ICAM-1的表达也明显增加（与假手术对照组相比P < 0.01）。生理盐水处理组的I/R区有强烈的白细胞积聚。用LOX-1抗体治疗大鼠可防止I/R诱导的LOX-1上调，并降低MMP-1和粘附分子表达以及白细胞募集。LOX-1抗体，但非特异性IgG，也减少心肌梗死面积（P < 0.01与生理盐水治疗I/R组）。为了探讨LOX-1和粘附分子表达之间的联系，我们检测了氧化应激敏感性p38丝裂原活化蛋白激酶（p38 MAPK）的表达。p38 MAPK活性在I/R期间增加（与假手术对照相比P < 0.01），LOX-1抗体的使用抑制p38 MAPK的活化（P < 0.01）。这些结果表明，心肌I/R上调LOX-1的表达，这通过p38 MAPK激活增加MMP-1和粘附分子的表达。LOX-1的抑制对心肌I/R损伤具有重要的保护作用。
A recently identified lectin-like oxidized low-density lipoprotein receptor (LOX-1) mediates endothelial cell injury and facilitates inflammatory cell adhesion. We studied the role of LOX-1 in myocardial ischemia-reperfusion (I/R) injury. Anesthetized Sprague-Dawley rats were subjected to 60 min of left coronary artery (LCA) ligation, followed by 60 min of reperfusion. Rats were treated with saline, LOX-1 blocking antibody JXT21 (10 mg/kg), or nonspecific anti-goat IgG (10 mg/kg) before I/R. Ten other rats underwent surgery without LCA ligation and served as a sham control group. LOX-1 expression was markedly increased during I/R (P < 0.01 vs. sham control group). Simultaneously, the expression of matrix metalloproteinase-1 (MMP-1) and adhesion molecules (P-selectin, VCAM-1, and ICAM-1) was also increased in the I/R area (P < 0.01 vs. sham control group). There was intense leukocyte accumulation in the I/R area in the saline-treated group. Treatment of rats with the LOX-1 antibody prevented I/R-induced upregulation of LOX-1 and reduced MMP-1 and adhesion molecule expression as well as leukocyte recruitment. LOX-1 antibody, but not nonspecific IgG, also reduced myocardial infarct size (P < 0.01 vs. saline-treated I/R group). To explore the link between LOX-1 and adhesion molecule expression, we measured expression of oxidative stress-sensitive p38 mitogen-activated protein kinase (p38 MAPK). The activity of p38 MAPK was increased during I/R (P < 0.01 vs. sham control), and use of LOX-1 antibody inhibited p38 MAPK activation (P < 0.01). These findings indicate that myocardial I/R upregulates LOX-1 expression, which through p38 MAPK activation increases the expression of MMP-1 and adhesion molecules. Inhibition of LOX-1 exerts an important protective effect against myocardial I/R injury.