Endothelial OCT4 is atheroprotective by preventing metabolic and phenotypic dysfunction . Issue 11 (24th March 2022)

• Record Type: Journal Article
• Authors: Shin, Junchul; Tkachenko, Svyatoslav; Chaklader, Malay; Pletz, Connor; Singh, Kanwardeep; Bulut, Gamze B; Han, Young min; Mitchell, Kelly; Baylis, Richard A; Kuzmin, Andrey A; Hu, Bo; Lathia, Justin D; Stenina-Adognravi, Olga; Podrez, Eugene; Byzova, Tatiana V; Owens, Gary K; Cherepanova, Olga A
• Is Part Of: Cardiovascular research. Volume 118:Issue 11(2022)
• Page Start: 2458
• Page End: 2477
• Publication Date: 2022-03-24
• Subjects: Atherosclerosis -- OCT4 -- ABCG2 -- ROS -- Heme; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac036
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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. Graphical Abstract: