Semaglutide treatment attenuates vessel remodelling in ApoE-/- mice following vascular injury and blood flow perturbation.
ApoE−/−, Apolipoprotein E knock-out
Atherosclerosis
GLP 1RA, Glucagon-like peptide 1 receptor agonist
Glucagon-like peptide 1 receptor agonists
IHC, Immunohistochemistry
ISH, In situ hybridisation
LCCA, Left common carotid artery
Phenotypic switching
Plaque erosion
SSP1, Osteopontin
Semaglutide
SoC, Standard of care
VSMC, Vascular smooth muscle cells
Vascular injury
Vascular smooth muscle cells
Journal
Atherosclerosis plus
ISSN: 2667-0895
Titre abrégé: Atheroscler Plus
Pays: Netherlands
ID NLM: 9918249514806676
Informations de publication
Date de publication:
Aug 2022
Aug 2022
Historique:
received:
19
04
2022
revised:
23
05
2022
accepted:
30
05
2022
entrez:
16
1
2023
pubmed:
17
1
2023
medline:
17
1
2023
Statut:
epublish
Résumé
Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque. In study A, we employed an electrical current to the carotid artery in ApoE-/- mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks. In study B, a constrictive cuff was added for 6 h at the site of the healed segment to induce a disturbance in blood flow. Compared to vehicle, semaglutide treatment reduced the intimal and medial area by ∼66% (p = 0.007) and ∼11% ( Semaglutide treatment reduced vessel remodelling following electrical injury and blood flow perturbation in an atheroprone mouse model. This effect appears to be driven by anti-inflammatory and -proliferative mechanisms independent of GLP-1 receptor-mediated signalling in the resident vascular cells. This mechanism of action may be important for cardiovascular protection.
Sections du résumé
Background and aims
UNASSIGNED
Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque.
Methods
UNASSIGNED
In study A, we employed an electrical current to the carotid artery in ApoE-/- mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks. In study B, a constrictive cuff was added for 6 h at the site of the healed segment to induce a disturbance in blood flow.
Results
UNASSIGNED
Compared to vehicle, semaglutide treatment reduced the intimal and medial area by ∼66% (p = 0.007) and ∼11% (
Conclusions
UNASSIGNED
Semaglutide treatment reduced vessel remodelling following electrical injury and blood flow perturbation in an atheroprone mouse model. This effect appears to be driven by anti-inflammatory and -proliferative mechanisms independent of GLP-1 receptor-mediated signalling in the resident vascular cells. This mechanism of action may be important for cardiovascular protection.
Identifiants
pubmed: 36644202
doi: 10.1016/j.athplu.2022.05.004
pii: S2667-0895(22)00016-5
pmc: PMC9833261
doi:
Types de publication
Journal Article
Langues
eng
Pagination
32-41Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors BR, LMV, MKEO, JCB, AU, CP, RKK, HH, LBK and MN are employees at Novo Nordisk. Novo Nordisk markets semaglutide for the treatment of diabetes and obesity. DMJ, GFS, and JL are present or former employees at University of Copenhagen and have collaborated with Novo Nordisk on this project.
Références
Circ Res. 2017 Jun 23;121(1):31-42
pubmed: 28428204
Diabetologia. 2014 Apr;57(4):781-4
pubmed: 24362727
Lancet. 2018 Oct 27;392(10157):1519-1529
pubmed: 30291013
N Engl J Med. 2016 Nov 10;375(19):1834-1844
pubmed: 27633186
Nat Genet. 2017 Jul;49(7):1113-1119
pubmed: 28530674
Digestion. 2016;94(4):199-214
pubmed: 27931035
Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1642-8
pubmed: 12377743
N Engl J Med. 2016 Jul 28;375(4):311-22
pubmed: 27295427
J Vasc Res. 2015;52(1):41-52
pubmed: 25966620
Endocrinol Diabetes Metab. 2021 Mar 19;4(3):e00234
pubmed: 34277961
Biochem Soc Trans. 2021 Nov 1;49(5):2101-2111
pubmed: 34495326
Endocrinology. 2014 Apr;155(4):1280-90
pubmed: 24467746
Diabetes Care. 2019 Dec;42(12):2262-2271
pubmed: 31530667
Nat Med. 2019 Aug;25(8):1280-1289
pubmed: 31359001
Arterioscler Thromb Vasc Biol. 2019 Jun;39(6):1006-1017
pubmed: 31043074
Lab Invest. 1991 Oct;65(4):459-70
pubmed: 1921335
Cells. 2019 Jun 14;8(6):
pubmed: 31207939
Diab Vasc Dis Res. 2013 Jul;10(4):353-60
pubmed: 23673376
JACC Basic Transl Sci. 2018 Nov 21;3(6):844-857
pubmed: 30623143
Circ Res. 2016 Feb 19;118(4):692-702
pubmed: 26892967
Biochem Biophys Res Commun. 2011 Feb 4;405(1):79-84
pubmed: 21215253
Curr Opin Lipidol. 2017 Oct;28(5):434-441
pubmed: 28682809
Nat Rev Cardiol. 2017 Jan;14(1):21-29
pubmed: 27762311
Am J Pathol. 1997 Feb;150(2):761-76
pubmed: 9033288
Pharmacol Rep. 2018 Feb;70(1):178-183
pubmed: 29414148
Diabetes Obes Metab. 2017 Jun;19(6):901-905
pubmed: 28105731
Nat Rev Cardiol. 2019 Dec;16(12):727-744
pubmed: 31243391
Lancet. 2019 Jul 13;394(10193):121-130
pubmed: 31189511
Cardiovasc Res. 2021 Sep 28;117(11):2326-2339
pubmed: 33576407
Cardiovasc Res. 2021 Nov 22;117(13):2652-2663
pubmed: 33751034
Circulation. 2018 May 15;137(20):2179-2183
pubmed: 29760228
Atherosclerosis. 2017 Jun;261:44-51
pubmed: 28445811
Circ Res. 2020 Dec 4;127(12):1552-1565
pubmed: 33040646