Aldehyde dehydrogenase 2 protects against abdominal aortic aneurysm formation by reducing reactive oxygen species, vascular inflammation, and apoptosis of vascular smooth muscle cells.
Aldehyde Dehydrogenase, Mitochondrial
/ physiology
Animals
Aortic Aneurysm, Abdominal
/ immunology
Apoptosis
Disease Models, Animal
Female
Inflammation
/ immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
/ immunology
Muscle, Smooth, Vascular
/ immunology
Oxidative Stress
Protective Agents
Reactive Oxygen Species
/ metabolism
4-hydroxy-2-nonenal
abdominal aortic aneurysm
aldehyde dehydrogenase 2
angiotensin II
reactive oxygen species
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
07
10
2019
revised:
04
05
2020
accepted:
07
05
2020
pubmed:
29
5
2020
medline:
2
3
2021
entrez:
29
5
2020
Statut:
ppublish
Résumé
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies aldehydes by converting them to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress. Increased oxidative stress plays a pivotal role in abdominal aortic aneurysm (AAA) pathogenesis. Reactive oxygen species (ROS) promote degradation of the extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) apoptosis. Reducing oxidative stress by an ALDH2 activator could have therapeutic potential for limiting AAA development. We hypothesized that ALDH2 deficiency could increase the risk for AAA by decreasing ROS elimination and that an ALDH2 activator could provide an alternative option for AAA treatment. The National Center for Biotechnology (NCBI) Gene Expression Omnibus (GEO) database was used. Human aortic smooth muscle cells (HASMCs) were used for the in vitro experiments. Gene-targeted ALDH2*2 KI knock-in mice on a C57BL/6J background and apolipoprotein E knockout (ApoE KO) mice were obtained. An animal model of AAA was constructed using osmotic minipumps to deliver 1000 ng/kg/min angiotensin II (AngII) for 28 days. Patients with AAA had significantly lower ALDH2 expression levels than normal subjects. ALDH2*2 KI mice were susceptible to AngII administration, exhibiting significantly increased AAA incidence rates and increased aortic diameters. Alda-1, an ALDH2 activator, reduced AngII-induced ROS production, NF-kB activation, and apoptosis in HASMCs. Alda-1 attenuated AngII-induced aneurysm formation and decreased aortic expansion in ApoE KO mice. We concluded that ALDH2 deficiency is associated with the development of AAAs in humans and a murine disease model. ALDH2 deficiency increases susceptibility to AngII-induced AAA formation by attenuating anti-ROS effects and increasing VSMC apoptosis and vascular inflammation. Alda-1 was shown to attenuate the progression of experimental AAA in a murine model.
Identifiants
pubmed: 32463165
doi: 10.1096/fj.201902550RRR
doi:
Substances chimiques
Protective Agents
0
Reactive Oxygen Species
0
ALDH2 protein, mouse
EC 1.2.1.3
Aldehyde Dehydrogenase, Mitochondrial
EC 1.2.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9498-9511Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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