한빛사논문
- 조회449
Ian A. Tamargo, PhD*; Kyung In Baek, PhD*; Chenbo Xu, MD; Dong Won Kang, MS; Yerin Kim, PhD; Aitor Andueza, PhD; Darian Williams, PhD; Catherine Demos, PhD; Nicolas Villa-Roel, PhD; Sandeep Kumar, PhD; Christian Park, MS; Rachel Choi; Janie Johnson, BS; Seowon Chang, BS; Paul Kim; Sheryl Tan; Kiyoung Jeong; Shoutaro Tsuji, PhD; Hanjoong Jo, PhD
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (I.A.T., K.I.B., C.X., D.W.K., Y.K., A.A., D.W., C.D., N.V.-R., S.K., C.P., R.C., J.J., S.C., P.K., S.T., K.J., H.J.). Molecular and Sys-tems Pharmacology Program (I.A.T., D.W., H.J.), Division of Cardiology, Department of Medicine (H.J.), Emory University, Atlanta, GA. Medical Technology & Clinical Engineering, Gunma University of Health and Welfare, Maebashi, Japan (S.T.).
*I.A. Tamargo and K.I. Baek contributed equally.
Correspondence to: Hanjoong Jo, PhD,
Abstract
Background: Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow, and stable flow (s-flow) protects against atherosclerosis by incompletely understood mechanisms.
Methods and results: Heart-of-glass 1 (HEG1) was identified from a single-cell RNA-sequencing study as an s-flow-induced endothelial gene, which we validated in vivo and in vitro. S-flow stimulated HEG1 protein translocation to the downstream side of the cell and release into the media, followed by increased messenger RNA and protein expression. HEG1 knockdown prevented s-flow-induced endothelial responses, including monocyte adhesion, permeability, and migration. Mechanistically, HEG1 knockdown prevented s-flow-induced KLF2/4 (Krüppel-like factor 2/4) expression by regulating its intracellular binding partner KRIT1 (Krev interaction trapped protein 1) and the MEKK3-MEK5-ERK5-MEF2 pathway in human aortic endothelial cells. Compared with littermate controls, tamoxifen-induced, endothelial-targeted HEG1 knockout (HEG1iECKO) mice exposed to hypercholesterolemia (by an adeno-associated virus-PCSK9 [proprotein convertase subtilisin/kexin type 9] injection and Western diet for 2 weeks) and partial carotid ligation developed advanced atherosclerotic plaques, featuring increased necrotic core area, thin-capped fibroatheroma, inflammation, and intraplaque hemorrhage. In a conventional Western diet model for 2 months, HEG1iECKO mice also showed an exacerbated atherosclerosis development in the arterial tree in both sexes and the aortic sinus in males but not in females. Moreover, endothelial HEG1 expression was reduced in human coronary arteries with advanced atherosclerotic plaques.
Conclusions: Our findings indicate that HEG1 is a novel mediator of atheroprotective endothelial responses to flow and a potential therapeutic target.
논문정보
- Research article
- 2023년 12월 (BRIC 등록일 2023-12-19)
- 국외 연구진
- 생명과학 > 세포생물학
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