Martínez-Revelles Sonia, García-Redondo Ana B, Avendaño María S, Varona Saray, Palao Teresa, Orriols Mar, Roque Fernanda R, Fortuño Ana, Touyz Rhian M, Martínez-González Jose, Salaices Mercedes, Rodríguez Cristina, Briones Ana M
1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain .
2 CIBER de Enfermedades Cardiovasculares , Spain .
Antioxid Redox Signal. 2017 Sep 1;27(7):379-397. doi: 10.1089/ars.2016.6642. Epub 2017 Jan 30.
Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces HO as a by-product. We addressed the interplay between LOX, oxidative stress, vessel stiffness, and elastin.
Angiotensin II (Ang II)-infused hypertensive mice and spontaneously hypertensive rats (SHR) showed increased vascular LOX expression and stiffness and an abnormal elastin structure. Mice over-expressing LOX in vascular smooth muscle cells (TgLOX) exhibited similar mechanical and elastin alterations to those of hypertensive models. LOX inhibition with β-aminopropionitrile (BAPN) attenuated mechanical and elastin alterations in TgLOX mice, Ang II-infused mice, and SHR. Arteries from TgLOX mice, Ang II-infused mice, and/or SHR exhibited increased vascular HO and O levels, NADPH oxidase activity, and/or mitochondrial dysfunction. BAPN prevented the higher oxidative stress in hypertensive models. Treatment of TgLOX and Ang II-infused mice and SHR with the mitochondrial-targeted superoxide dismutase mimetic mito-TEMPO, the antioxidant apocynin, or the HO scavenger polyethylene glycol-conjugated catalase (PEG-catalase) reduced oxidative stress, vascular stiffness, and elastin alterations. Vascular p38 mitogen-activated protein kinase (p38MAPK) activation was increased in Ang II-infused and TgLOX mice and this effect was prevented by BAPN, mito-TEMPO, or PEG-catalase. SB203580, the p38MAPK inhibitor, normalized vessel stiffness and elastin structure in TgLOX mice.
We identify LOX as a novel source of vascular reactive oxygen species and a new pathway involved in vascular stiffness and elastin remodeling in hypertension.
LOX up-regulation is associated with enhanced oxidative stress that promotes p38MAPK activation, elastin structural alterations, and vascular stiffness. This pathway contributes to vascular abnormalities in hypertension. Antioxid. Redox Signal. 27, 379-397.
血管僵硬、结构弹性蛋白异常以及氧化应激增加是高血压的特征。赖氨酰氧化酶（LOX）是一种弹性蛋白交联酶，其副产物为过氧化氢（HO）。我们研究了LOX、氧化应激、血管僵硬和弹性蛋白之间的相互作用。
输注血管紧张素II（Ang II）的高血压小鼠和自发性高血压大鼠（SHR）的血管LOX表达和僵硬程度增加，弹性蛋白结构异常。在血管平滑肌细胞中过表达LOX的小鼠（TgLOX）表现出与高血压模型相似的力学和弹性蛋白改变。用β-氨基丙腈（BAPN）抑制LOX可减轻TgLOX小鼠、输注Ang II的小鼠和SHR的力学和弹性蛋白改变。来自TgLOX小鼠、输注Ang II的小鼠和/或SHR的动脉显示血管HO和氧水平升高、NADPH氧化酶活性增加和/或线粒体功能障碍。BAPN可预防高血压模型中较高的氧化应激。用线粒体靶向超氧化物歧化酶模拟物线粒体-TEMPO、抗氧化剂阿朴吗啡或HO清除剂聚乙二醇偶联过氧化氢酶（PEG-过氧化氢酶）治疗TgLOX小鼠、输注Ang II的小鼠和SHR可降低氧化应激、血管僵硬和弹性蛋白改变。在输注Ang II的小鼠和TgLOX小鼠中，血管p38丝裂原活化蛋白激酶（p38MAPK）的激活增加，而BAPN、线粒体-TEMPO或PEG-过氧化氢酶可阻止这种作用。p38MAPK抑制剂SB203580可使TgLOX小鼠的血管僵硬和弹性蛋白结构恢复正常。
我们确定LOX是血管活性氧的新来源，也是高血压中涉及血管僵硬和弹性蛋白重塑的新途径。
LOX上调与氧化应激增强有关，氧化应激促进p38MAPK激活、弹性蛋白结构改变和血管僵硬。该途径导致高血压中的血管异常。《抗氧化与氧化还原信号》27, 379 - 397。
