期刊
CARDIOVASCULAR RESEARCH
卷 118, 期 11, 页码 2458-2477出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvac036
关键词
Atherosclerosis; OCT4; ABCG2; ROS; Heme
资金
- American Heart Association Innovative Research Grant [17IRG33370017]
- NIH [R56HL148025, R01 HL071625, R01 HL145536, R01 HL136314]
Recent studies have shown that OCT4 plays a critical atheroprotective role in smooth muscle cells, and also regulates plaque characteristics in endothelial cells, making it a potential target for novel therapeutics.
Aims Until recently, the pluripotency factor Octamer (ATGCAAAT)-binding transcriptional factor 4 (OCT4) was believed to be dispensable in adult somatic cells. However, our recent studies provided clear evidence that OCT4 has a critical atheroprotective role in smooth muscle cells. Here, we asked if OCT4 might play a functional role in regulating endothelial cell (EC) phenotypic modulations in atherosclerosis. Methods and results Specifically, we show that EC-specific Oct4 knockout resulted in increased lipid, LGALS3(+) cell accumulation, and altered plaque characteristics consistent with decreased plaque stability. A combination of single-cell RNA sequencing and EC-lineage-tracing studies revealed increased EC activation, endothelial-to-mesenchymal transitions, plaque neovascularization, and mitochondrial dysfunction in the absence of OCT4. Furthermore, we show that the adenosine triphosphate (ATP) transporter, ATP-binding cassette (ABC) transporter G2 (ABCG2), is a direct target of OCT4 in EC and establish for the first time that the OCT4/ABCG2 axis maintains EC metabolic homeostasis by regulating intracellular heme accumulation and related reactive oxygen species production, which, in turn, contributes to atherogenesis. Conclusions These results provide the first direct evidence that OCT4 has a protective metabolic function in EC and identifies vascular OCT4 and its signalling axis as a potential target for novel therapeutics.
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