LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse.
LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse.
复制标题
作者：
我们假设，凝集素样氧化低密度脂蛋白受体-1（LOX-1）的缺失可能会抑制氧化应激信号，减少胶原积累，减轻慢性缺血后的心脏重塑。LOX-1的激活在急性缺血期间的炎症、凋亡和胶原信号的发展中起重要作用。对野生型和LOX-1敲除（KO）小鼠进行左冠状动脉闭塞3周。分析了心脏肥大、纤维化相关信号（IV型胶原、1型胶原和纤连蛋白）和氧化剂负荷（烟酰胺腺嘌呤二核苷酸磷酸氧化酶表达、丝裂原活化蛋白激酶活性和左心室（LV）组织硫代巴比妥酸反应物质）的标志物。在体外实验中，将血管紧张素II（Ang II）1型受体（AT 1 R）或2型受体（AT 2 R）基因转染HL-1心肌细胞，以确定其在心肌细胞肥大中的作用。LOX-1 KO小鼠在慢性缺血的3周期间的存活率提高了25%。LOX-1缺失可减少胶原沉积和心肌细胞肥大（约75%），并降低氧化负荷和AT 1 R上调（均P<0.05）。LOX-1基因敲除小鼠心肌组织中去整合素和金属蛋白酶10（ADAM 10）、去整合素和金属蛋白酶17（ADAM 17）的表达及基质金属蛋白酶2（MMP 2）活性均显著升高（P<0.05），AT 2 R的表达也显著升高（P<0.05）。心脏重构的减弱与心脏血流动力学（LV ±dp/dt和心脏射血分数）的改善相关。体外研究表明，是AT 1 R而不是AT 2 R过表达诱导心肌细胞肥大。我们首次证明LOX-1缺失降低了氧化应激和相关的细胞内信号传导，这导致了涉及AT 1 R和LOX-1的正反馈回路的衰减。这导致慢性心脏重塑减少。
We hypothesized that lectin-like oxidized LDL receptor-1 (LOX-1) deletion may inhibit oxidative stress signals, reduce collagen accumulation and attenuate cardiac remodeling after chronic ischemia. Activation of LOX-1 plays a significant role in the development of inflammation, apoptosis and collagen signals during acute ischemia. Wild-type and LOX-1 knockout (KO) mice were subjected to occlusion of left coronary artery for 3 weeks. Markers of cardiac hypertrophy, fibrosis-related signals (collagen IV, collagen-1 and fibronectin) and oxidant load (nicotinamide adenine dinucleotide phosphate oxidase expression, activity of mitogen-activated protein kinases and left ventricular (LV) tissue thiobarbituric acid reactive substances) were analyzed. In in vitro experiments, HL-1 cardiomyocytes were transfected with angiotensin II (Ang II) type 1 receptor (AT1R) or type 2 receptor (AT2R) genes to determine their role in the cardiomyocyte hypertrophy. LOX-1 KO mice had 25% improvement in survival over the 3-week period of chronic ischemia. LOX-1 deletion reduced collagen deposition and cardiomyocyte hypertrophy (~75%) in association with a decrease in oxidant load and AT1R upregulation (all P<0.05). The LOX-1 KO mice hearts exhibited a disintegrin and metalloproteinase 10 (ADAM10) and a disintegrin and metalloproteinase 17 (ADAM17) expression and matrix metalloproteinase 2 activity, and increased AT2R expression (P<0.05). Attenuation of cardiac remodeling was associated with improved cardiac hemodynamics (LV ±dp/dt and cardiac ejection fraction). In vitro studies showed that it is AT1R, and not AT2R overexpression that induces cardiomyocyte hypertrophy. We demonstrate for the first time that LOX-1 deletion reduces oxidative stress and related intracellular signaling, which leads to attenuation of the positive feedback loop involving AT1R and LOX-1. This results in reduced chronic cardiac remodeling.
登录
查看更多内容
DOI：
10.1161/circimaging.109.896654
发表时间：
2010-07
期刊：
Circulation. Cardiovascular imaging
影响因子：
--
作者：
Li D;Patel AR;Klibanov AL;Kramer CM;Ruiz M;Kang BY;Mehta JL;Beller GA;Glover DK;Meyer CH
通讯作者：
Meyer CH
影响因子：
4.8
作者：
Hu, Changping;Dandapat, Abhijit;Mehta, Jawahar L.
通讯作者：
Mehta, Jawahar L.
影响因子：
8.3
作者：
Hu, Changping;Dandapat, Abhijit;Mehta, Jawahar L.
通讯作者：
Mehta, Jawahar L.
影响因子：
20.1
作者：
Mehta, Jawahar L.;Sanada, Nobuhito;Sawamura, Tatsuya
通讯作者：
Sawamura, Tatsuya
影响因子：
37.8
作者：
Iwai-Kanai, E;Hasegawa, K;Sasayama, S
通讯作者：
Sasayama, S