Smooth muscle α-actin missense variant promotes atherosclerosis through modulation of intracellular cholesterol in smooth muscle cells.
Mice
Animals
Plaque, Atherosclerotic
/ complications
Actins
/ metabolism
Mice, Knockout, ApoE
Atherosclerosis
/ etiology
Cholesterol
/ metabolism
Hyperlipidemias
/ complications
Myocytes, Smooth Muscle
/ metabolism
Muscle, Smooth
/ metabolism
Apolipoproteins E
/ genetics
Mice, Inbred C57BL
Mice, Knockout
Atherosclerosis
Cholesterol
Phenotypic switching
Smooth muscle cell
Smooth muscle α-actin
Journal
European heart journal
ISSN: 1522-9645
Titre abrégé: Eur Heart J
Pays: England
ID NLM: 8006263
Informations de publication
Date de publication:
01 08 2023
01 08 2023
Historique:
received:
29
11
2022
revised:
15
03
2023
accepted:
24
05
2023
medline:
3
8
2023
pubmed:
28
6
2023
entrez:
28
6
2023
Statut:
ppublish
Résumé
The variant p.Arg149Cys in ACTA2, which encodes smooth muscle cell (SMC)-specific α-actin, predisposes to thoracic aortic disease and early onset coronary artery disease in individuals without cardiovascular risk factors. This study investigated how this variant drives increased atherosclerosis. Apoe-/- mice with and without the variant were fed a high-fat diet for 12 weeks, followed by evaluation of atherosclerotic plaque formation and single-cell transcriptomics analysis. SMCs explanted from Acta2R149C/+ and wildtype (WT) ascending aortas were used to investigate atherosclerosis-associated SMC phenotypic modulation. Hyperlipidemic Acta2R149C/+Apoe-/- mice have a 2.5-fold increase in atherosclerotic plaque burden compared to Apoe-/- mice with no differences in serum lipid levels. At the cellular level, misfolding of the R149C α-actin activates heat shock factor 1, which increases endogenous cholesterol biosynthesis and intracellular cholesterol levels through increased HMG-CoA reductase (HMG-CoAR) expression and activity. The increased cellular cholesterol in Acta2R149C/+ SMCs induces endoplasmic reticulum stress and activates PERK-ATF4-KLF4 signaling to drive atherosclerosis-associated phenotypic modulation in the absence of exogenous cholesterol, while WT cells require higher levels of exogenous cholesterol to drive phenotypic modulation. Treatment with the HMG-CoAR inhibitor pravastatin successfully reverses the increased atherosclerotic plaque burden in Acta2R149C/+Apoe-/- mice. These data establish a novel mechanism by which a pathogenic missense variant in a smooth muscle-specific contractile protein predisposes to atherosclerosis in individuals without hypercholesterolemia or other risk factors. The results emphasize the role of increased intracellular cholesterol levels in driving SMC phenotypic modulation and atherosclerotic plaque burden.
Identifiants
pubmed: 37377039
pii: 7209229
doi: 10.1093/eurheartj/ehad373
pmc: PMC10393072
doi:
Substances chimiques
Actins
0
Cholesterol
97C5T2UQ7J
Apolipoproteins E
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2713-2726Subventions
Organisme : NIH HHS
ID : S10OD023469
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146583
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM120011
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114356
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006348
Pays : United States
Organisme : NIH HHS
ID : S10 OD025240
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY002520
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
Références
FEBS Lett. 2009 Feb 18;583(4):782-6
pubmed: 19183552
Stroke. 2010 Dec;41(12):2782-5
pubmed: 21030702
Cardiovasc Res. 2016 Jul 1;111(1):74-83
pubmed: 27131506
Wien Med Wochenschr. 2018 Sep;168(11-12):280-285
pubmed: 29488036
J Am Coll Cardiol. 2017 Dec 19;70(24):2979-2991
pubmed: 29241485
PLoS Biol. 2014 Nov 18;12(11):e1001998
pubmed: 25406061
PLoS Genet. 2017 Jul 5;13(7):e1006849
pubmed: 28678786
J Biol Chem. 2021 Dec;297(6):101228
pubmed: 34600884
Circ Res. 2018 Feb 2;122(3):433-443
pubmed: 29212778
Sci Rep. 2021 Mar 29;11(1):7025
pubmed: 33782520
Cancers (Basel). 2019 Sep 13;11(9):
pubmed: 31540279
Am J Pathol. 2003 May;162(5):1669-76
pubmed: 12707051
Am J Hum Genet. 2009 May;84(5):617-27
pubmed: 19409525
Circ Res. 2015 May 22;116(11):1736-43
pubmed: 25872946
Circulation. 2007 Aug 7;116(6):613-8
pubmed: 17664373
Circulation. 2020 Nov 24;142(21):2045-2059
pubmed: 32674599
EMBO Mol Med. 2019 Apr;11(4):
pubmed: 30862662
J Pediatr. 2005 Mar;146(3):336-41
pubmed: 15756215
Cardiovasc Res. 2018 Jul 15;114(9):1241-1257
pubmed: 29617720
Nat Med. 2019 Aug;25(8):1280-1289
pubmed: 31359001
Cell Rep. 2014 Nov 6;9(3):955-66
pubmed: 25437552
Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):302-316
pubmed: 33028096
Nat Genet. 2007 Dec;39(12):1488-93
pubmed: 17994018
Int J Mol Sci. 2019 Nov 19;20(22):
pubmed: 31752429
Sci Rep. 2020 Apr 6;10(1):5951
pubmed: 32249802
Mol Cells. 2015 Oct;38(10):851-8
pubmed: 26442866
Arterioscler Thromb Vasc Biol. 2017 Sep;37(9):e131-e157
pubmed: 28729366
Circulation. 2020 Nov 24;142(21):2060-2075
pubmed: 32962412
Nat Cell Biol. 2003 Sep;5(9):781-92
pubmed: 12907943
PLoS One. 2011;6(11):e27841
pubmed: 22140470
Arterioscler Thromb Vasc Biol. 2022 Aug;42(8):1005-1022
pubmed: 35708026
Ann Intern Med. 1999 Sep 7;131(5):363-75
pubmed: 10475890
Science. 1986 Apr 4;232(4746):34-47
pubmed: 3513311
J Clin Invest. 2001 May;107(10):1263-73
pubmed: 11375416
Cell Stress Chaperones. 2006 Winter;11(4):379-89
pubmed: 17278886
Nat Med. 2015 Jun;21(6):628-37
pubmed: 25985364