Department of Biotechnology, University of Siena, 53100-Siena, Italy.
J Cell Sci. 2013 May 1;126(Pt 9):1952-61. doi: 10.1242/jcs.117184. Epub 2013 Feb 27.
Amyloid β peptides (Aβ1-40 and Aβ1-42) cause cerebral degeneration by impairing the activity of angiogenic factors and inducing apoptosis and senescence in the endothelium. Amyloid peptides are known to induce oxidative stress. Impairment of mitochondrial aldehyde dehydrogenase 2 (ALDH2) following oxidative stress, results in accumulation of toxic aldehydes, particularly 4-hydroxynoneal (4-HNE). We sought to determine the role of mitochondrial ALDH2 in Aβ-related impairment of angiogenesis. We hypothesized that by increasing the detoxification activity of ALDH2 we would reduce Aβ-driven endothelial injuries and restore angiogenesis. We used a selective ALDH2 activator, Alda-1, assessing its ability to repair mitochondrial dysfunction in the endothelium. Treatment of human endothelial cells with Aβ1-40 (5-50 µM) induced loss of mitochondrial membrane potential, increased cytochrome c release and ROS accumulation. These events were associated with 4-HNE accumulation and decrease in ALDH2 activity (40%), and resulted in disassembly of endothelial junctions, as evidenced by β-catenin phosphorylation, disorganization of adherens and tight junctions, and by disruption of pseudocapillary formation. Alda-1 (10-40 µM) abolished Aβ-induced 4-HNE accumulation, apoptosis and vascular leakiness, fully restoring the pro-angiogenic endothelial phenotype and responses to FGF-2. Our data document that mitochondrial ALDH2 in the endothelium is a target for the vascular effect of Aβ, including loss of barrier function and angiogenesis. ALDH2 activation, by restoring mitochondrial functions in the endothelium, prevents Aβ-induced dysfunction and anti-angiogenic effects. Thus, agents activating ALDH2 may reduce endothelial injuries including those occurring in cerebral amyloid angiopathy, preserving the angiogenic potential of the endothelium.
淀粉样β肽（Aβ1-40 和 Aβ1-42）通过损害血管生成因子的活性并诱导内皮细胞凋亡和衰老，导致大脑退化。已知淀粉样肽会引起氧化应激。氧化应激后线粒体乙醛脱氢酶 2（ALDH2）的损伤导致有毒醛的积累，特别是 4-羟壬烯醛（4-HNE）。我们试图确定线粒体 ALDH2 在与 Aβ 相关的血管生成损伤中的作用。我们假设通过增加 ALDH2 的解毒活性，我们将减少 Aβ 驱动的内皮损伤并恢复血管生成。我们使用了一种选择性的 ALDH2 激活剂，Alda-1，评估其修复内皮细胞中线粒体功能障碍的能力。用 Aβ1-40（5-50 µM）处理人内皮细胞会诱导线粒体膜电位丧失、细胞色素 c 释放和 ROS 积累增加。这些事件与 4-HNE 积累和 ALDH2 活性（40%）下降有关，导致内皮连接解体，β-连环蛋白磷酸化、黏附连接和紧密连接紊乱以及假毛细血管形成中断可证明这一点。Alda-1（10-40 µM）消除了 Aβ 诱导的 4-HNE 积累、凋亡和血管通透性增加，完全恢复了促血管生成的内皮表型和对 FGF-2 的反应。我们的数据表明，内皮细胞中的线粒体 ALDH2 是 Aβ 血管作用的靶点，包括屏障功能丧失和血管生成。ALDH2 激活通过恢复内皮细胞中线粒体功能，防止 Aβ 诱导的功能障碍和抗血管生成作用。因此，激活 ALDH2 的药物可能会减少包括在脑淀粉样血管病中发生的内皮损伤，从而保持内皮的血管生成潜力。
