Substitution of SERCA2 Cys
SERCA2 Cys674
aortic aneurysm
apoptosis
endoplasmic reticulum stress
phenotypic transition
smooth muscle cells
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
revised:
08
04
2022
received:
15
11
2021
accepted:
10
04
2022
pubmed:
2
5
2022
medline:
18
8
2022
entrez:
1
5
2022
Statut:
ppublish
Résumé
The Cys Heterozygous SERCA2 C674S knock-in (SKI) mice, in which half of C674 was replaced by serine, were used to mimic partially irreversible oxidation of C674 thiol. The aortas of SKI mice and their littermate wild-type mice under an LDL receptor-deficient background were collected for histological and immunohistochemical analysis. Cultured aortic SMCs were used for protein expression, apoptosis analysis, and cell function studies. The substitution of SERCA2 C674 caused endoplasmic reticulum (ER) stress and induced SMC apoptosis. The inhibition of ER stress by 4-phenylbutyric acid (4-PBA) in SKI aortic SMCs decreased the expression of marker proteins for cell apoptosis as well as phenotypic transition, and prevented cell apoptosis, proliferation, migration, and macrophage adhesion to SMCs. 4-PBA also ameliorated angiotensin II-induced aortic aneurysm in SKI mice. The irreversible oxidation of SERCA2 C674 promotes the development of aortic aneurysm by inducing ER stress and subsequent SMC apoptosis. Our study illustrates that ER stress caused by oxidative inactivation of C674 is related to the pathogenesis of aortic aneurysm. Therefore, ER stress and SERCA2 are potential therapeutic targets for treating aortic aneurysm.
Sections du résumé
BACKGROUND AND PURPOSE
The Cys
EXPERIMENTAL APPROACH
Heterozygous SERCA2 C674S knock-in (SKI) mice, in which half of C674 was replaced by serine, were used to mimic partially irreversible oxidation of C674 thiol. The aortas of SKI mice and their littermate wild-type mice under an LDL receptor-deficient background were collected for histological and immunohistochemical analysis. Cultured aortic SMCs were used for protein expression, apoptosis analysis, and cell function studies.
KEY RESULTS
The substitution of SERCA2 C674 caused endoplasmic reticulum (ER) stress and induced SMC apoptosis. The inhibition of ER stress by 4-phenylbutyric acid (4-PBA) in SKI aortic SMCs decreased the expression of marker proteins for cell apoptosis as well as phenotypic transition, and prevented cell apoptosis, proliferation, migration, and macrophage adhesion to SMCs. 4-PBA also ameliorated angiotensin II-induced aortic aneurysm in SKI mice.
CONCLUSIONS AND IMPLICATIONS
The irreversible oxidation of SERCA2 C674 promotes the development of aortic aneurysm by inducing ER stress and subsequent SMC apoptosis. Our study illustrates that ER stress caused by oxidative inactivation of C674 is related to the pathogenesis of aortic aneurysm. Therefore, ER stress and SERCA2 are potential therapeutic targets for treating aortic aneurysm.
Substances chimiques
Angiotensin II
11128-99-7
Sarcoplasmic Reticulum Calcium-Transporting ATPases
EC 3.6.3.8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4423-4439Subventions
Organisme : British Heart Foundation
ID : FS/17/2/32559
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/21/10595
Pays : United Kingdom
Informations de copyright
© 2022 British Pharmacological Society.
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