PRDM16 regulates smooth muscle cell identity and atherosclerotic plaque composition

Vascular smooth muscle cells (SMCs) undergo phenotype switching to acquire various fates in response to pathological stimuli. Among these, 'synthetic' SMCs-defined by migration, proliferation and extracellular matrix production-accumulate in atherosclerotic lesions and contribute to fibrou...

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Vydáno v:	Nature cardiovascular research Ročník 4; číslo 11; s. 1573
Hlavní autoři:	Tan, Josephine M E, Cheng, Lan, Calhoun, Ryan P, Weller, Angela H, Drareni, Karima, Fong, Skylar, Barbara, Eirlys, Lim, Hee-Woong, Xue, Chenyi, Winter, Hanna, Auguste, Gaëlle, Miller, Clint L, Reilly, Muredach P, Maegdefessel, Lars, Lutgens, Esther, Seale, Patrick
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England 01.11.2025
Témata:	Animals Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - pathology Cell Movement Cell Proliferation Cells, Cultured Disease Models, Animal DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Fibrosis Foam Cells - metabolism Foam Cells - pathology Gene Expression Regulation Humans Male Mice Mice, Inbred C57BL Mice, Knockout Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Phenotype Plaque, Atherosclerotic Transcription Factors - deficiency Transcription Factors - genetics Transcription Factors - metabolism
ISSN:	2731-0590, 2731-0590
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Popis
Shrnutí:	Vascular smooth muscle cells (SMCs) undergo phenotype switching to acquire various fates in response to pathological stimuli. Among these, 'synthetic' SMCs-defined by migration, proliferation and extracellular matrix production-accumulate in atherosclerotic lesions and contribute to fibrous cap formation. The mechanisms driving this synthetic transition remain unclear. Here we identify PRDM16, a gene linked to cardiovascular disease, as a critical transcriptional repressor of the synthetic SMC phenotype. PRDM16 expression declined during SMC modulation, and its deletion in mice induced a synthetic program across all SMC subtypes even without pathological stimuli. Under atherogenic conditions, PRDM16 deficiency resulted in the formation of fibroproliferative plaques with more synthetic SMCs and fewer foam cells. Conversely, enforced PRDM16 expression suppressed SMC migration, proliferation and fibrosis. Mechanistically, PRDM16 occupied chromatin and suppressed activating marks at synthetic loci. These findings establish PRDM16 as a gatekeeper of SMC fate and reveal its role in shaping atherosclerotic plaque composition.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2731-0590 2731-0590
DOI:	10.1038/s44161-025-00737-8