한빛사논문
- 조회555
Junchul Shin 1†, Svyatoslav Tkachenko2†, Malay Chaklader1†, Connor Pletz1, Kanwardeep Singh1, Gamze B. Bulut3, Young-min Han4, Kelly Mitchell1, Richard A. Baylis3, Andrey A. Kuzmin5, Bo Hu2, Justin D. Lathia1, Olga Stenina-Adognravi1, Eugene Podrez6, Tatiana V. Byzova7, Gary K. Owens3,8, and Olga A. Cherepanova 1*
1Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 2Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 3Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA; 4Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA; 5Russian Academy of Sciences, Institute of Cytology, St Petersburg, Russian Federation; 6Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 7Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; and 8Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA
* Corresponding author.
† Authors contributed equally.
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.
논문정보
- Research article
- 2022년 07월 (BRIC 등록일 2022-10-05)
- 국외 연구진
- 생명과학 > 분자생물학
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