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Mitochondrial aldehyde dehydrogenase-2 activation prevents β amyloids induced endothelial cell dysfunction and restores angiogenesis
- Publication Year :
- 2013
-
Abstract
- Amyloid β peptides (Aβ1-40 and Aβ1-42) cause cerebral degeneration also by exerting antiangiogenic properties, as impairment of angiogenic factors activity and induction of 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 mithocondrial 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 mithocondrial 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 endothelium is a target for the vascular effect of Aβ including loss of barrier function and angiogenesis. ALDH2 activation, by restoring mitochondrial functions in endothelium, prevents Aβ-induced dysfunction and antiangiogenic effects. Thus, agents activating ALDH2 may reduce endothelial injuries including those occurring in cerebral amyloid angiopathy, preserving the angiogenic potential of the endothelium.
- Subjects :
- Endothelium
Angiogenesis
Enzyme Activators
Neovascularization, Physiologic
Mitochondrion
Biology
Membrane Potentials
Mitochondrial Proteins
Adherens junction
Human Umbilical Vein Endothelial Cells
medicine
Humans
Benzodioxoles
Phosphorylation
beta Catenin
ALDH2
Amyloid beta-Peptides
Aldehyde Dehydrogenase, Mitochondrial
Cerebral degeneration
Cell Biology
Aldehyde Dehydrogenase
medicine.disease
Peptide Fragments
Cell biology
Enzyme Activation
Endothelial stem cell
Oxidative Stress
medicine.anatomical_structure
Biochemistry
Benzamides
Cerebral amyloid angiopathy
Reactive Oxygen Species
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....b0151aecd774acae39323f2e89a29640