Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 May 1;115(18):4672-4677. doi: 10.1073/pnas.1712918115. Epub 2018 Mar 27.

Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium.

Author information

1
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, 03722 Seoul, Korea.
2
Division of Nutrition and Metabolism Research Group, Korea Food Research Institute, 13539 Gyeonggi-do, Korea.
3
Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Korea.
4
Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University College of Human Medicine, MI 49503.
5
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, 13539 Seoul, Korea chhoonha@amc.seoul.kr shpark0530@yuhs.ac yhgeun@yuhs.ac.
6
Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Korea; chhoonha@amc.seoul.kr shpark0530@yuhs.ac yhgeun@yuhs.ac.
7
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, 03722 Seoul, Korea; chhoonha@amc.seoul.kr shpark0530@yuhs.ac yhgeun@yuhs.ac.

Abstract

Programmed cell death 5 (PDCD5) has been associated with human cancers as a regulator of cell death; however, the role of PDCD5 in the endothelium has not been revealed. Thus, we investigated whether PDCD5 regulates protein kinase B (PKB/AKT)-endothelial nitric oxide synthase (eNOS)-dependent signal transduction in the endothelium and affects atherosclerosis. Endothelial-specific PDCD5 knockout mice showed significantly reduced vascular remodeling compared with wild-type (WT) mice after partial carotid ligation. WT PDCD5 competitively inhibited interaction between histone deacetylase 3 (HDAC3) and AKT, but PDCD5L6R, an HDAC3-binding-deficient mutant, did not. Knockdown of PDCD5 accelerated HDAC3-AKT interaction, AKT and eNOS phosphorylation, and nitric oxide (NO) production in human umbilical vein endothelial cells. Moreover, we found that serum PDCD5 levels reflect endothelial NO production and are correlated with diabetes mellitus, high-density lipoprotein cholesterol, and coronary calcium in human samples obtained from the cardiovascular high-risk cohort. Therefore, we conclude that PDCD5 is associated with endothelial dysfunction and may be a novel therapeutic target in atherosclerosis.

KEYWORDS:

AKT; HDAC3; PDCD5; atherosclerosis; endothelium

Comment in

PMID:
29588416
PMCID:
PMC5939060
DOI:
10.1073/pnas.1712918115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center