Preventing Cholesterol-Induced Perk (Protein Kinase RNA-Like Endoplasmic Reticulum Kinase) Signaling in Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation.
diet, high-fat
hypercholesterolemia
muscle, smooth, vascular
plaque, atherosclerotic
Journal
Arteriosclerosis, thrombosis, and vascular biology
ISSN: 1524-4636
Titre abrégé: Arterioscler Thromb Vasc Biol
Pays: United States
ID NLM: 9505803
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
pubmed:
17
6
2022
medline:
30
7
2022
entrez:
16
6
2022
Statut:
ppublish
Résumé
Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling. We generated an SMC-specific SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 clusters of modulated SMCs in hyperlipidemic mice, one of which is absent when Our results indicate that hypercholesterolemia drives both Perk-dependent and Perk-independent SMC modulation and that deficiency of Perk significantly blocks atherosclerotic plaque formation.
Sections du résumé
BACKGROUND
Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling.
METHODS
We generated an SMC-specific
RESULTS
SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 clusters of modulated SMCs in hyperlipidemic mice, one of which is absent when
CONCLUSIONS
Our results indicate that hypercholesterolemia drives both Perk-dependent and Perk-independent SMC modulation and that deficiency of Perk significantly blocks atherosclerotic plaque formation.
Identifiants
pubmed: 35708026
doi: 10.1161/ATVBAHA.121.317451
pmc: PMC9311463
doi:
Substances chimiques
Cholesterol
97C5T2UQ7J
PERK kinase
EC 2.7.11.1
eIF-2 Kinase
EC 2.7.11.1
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
1005-1022Subventions
Organisme : NEI NIH HHS
ID : P30 EY002520
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM120011
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR003169
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006348
Pays : United States
Organisme : NIH HHS
ID : S10 OD023469
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114356
Pays : United States
Organisme : NIH HHS
ID : S10 OD025240
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146583
Pays : United States
Références
BMC Genomics. 2018 Jun 19;19(1):477
pubmed: 29914354
Arterioscler Thromb Vasc Biol. 2021 Jun;41(6):e354-e368
pubmed: 33792344
Cell Tissue Res. 2012 Jan;347(1):155-75
pubmed: 21626289
PLoS Genet. 2013;9(7):e1003652
pubmed: 23874238
JACC Basic Transl Sci. 2020 Feb 19;5(3):245-263
pubmed: 32215348
Atherosclerosis. 2009 Nov;207(1):123-30
pubmed: 19467656
Proc Natl Acad Sci U S A. 2020 Jul 7;117(27):15818-15826
pubmed: 32541024
Nature. 2011 May 19;473(7347):317-25
pubmed: 21593864
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1191-1201
pubmed: 29599133
J Cell Biol. 2005 Oct 10;171(1):61-73
pubmed: 16203857
Genes Dev. 1998 Jun 15;12(12):1812-24
pubmed: 9637683
J Cell Biol. 2009 Aug 10;186(3):323-31
pubmed: 19651891
Diabetes. 2021 Jan;70(1):76-90
pubmed: 33139329
Lab Invest. 2019 Mar;99(3):290-304
pubmed: 29795127
Circulation. 2020 Jan 7;141(1):42-66
pubmed: 31887080
Circulation. 2020 Nov 24;142(21):2045-2059
pubmed: 32674599
Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1395-E1404
pubmed: 28137856
EMBO Mol Med. 2019 Apr;11(4):
pubmed: 30862662
Science. 2006 Jul 7;313(5783):104-7
pubmed: 16825573
Innovation (Camb). 2021 Jul 01;2(3):100141
pubmed: 34557778
Genome Res. 2017 Nov;27(11):1816-1829
pubmed: 29025894
Nat Med. 2019 Aug;25(8):1280-1289
pubmed: 31359001
Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):302-316
pubmed: 33028096
Arterioscler Thromb Vasc Biol. 2017 Sep;37(9):e131-e157
pubmed: 28729366
Circulation. 2020 Nov 24;142(21):2060-2075
pubmed: 32962412
Cell Metab. 2009 May;9(5):474-81
pubmed: 19416717
Nucleic Acids Res. 2019 Jul 2;47(W1):W212-W224
pubmed: 31114921
Nat Commun. 2015 Jun 17;6:7339
pubmed: 26081744
Nat Biotechnol. 2019 Dec;37(12):1482-1492
pubmed: 31796933
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
J Biol Chem. 2011 Sep 2;286(35):30624-30635
pubmed: 21757691
Nat Cell Biol. 2003 Sep;5(9):781-92
pubmed: 12907943
Neuron. 2020 Mar 4;105(5):855-866.e5
pubmed: 31924446
Nat Methods. 2018 Apr;15(4):255-261
pubmed: 29481549
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
Nat Genet. 2011 Mar 06;43(4):333-8
pubmed: 21378990
Front Cell Dev Biol. 2021 May 19;9:689469
pubmed: 34095155
PLoS Genet. 2015 May 28;11(5):e1005155
pubmed: 26020946
Nat Commun. 2020 Mar 5;11(1):1201
pubmed: 32139671
Mol Biol Cell. 1999 Nov;10(11):3787-99
pubmed: 10564271
Genome Biol. 2015 Dec 10;16:278
pubmed: 26653891
Circ Res. 2015 May 22;116(11):1736-43
pubmed: 25872946
Nature. 2002 Jan 3;415(6867):92-6
pubmed: 11780124
Circulation. 2020 Aug 11;142(6):575-590
pubmed: 32441123
Elife. 2018 Dec 24;7:
pubmed: 30582518
Nat Med. 2015 Jun;21(6):628-37
pubmed: 25985364