Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium.
Seung-Hyun LeeJaesung SeoSoo-Yeon ParkMi-Hyeon JeongHyo-Kyoung ChoiChan Joo LeeMi Jeong KimGaram GukSooYeon LeeHyewon ParkJae-Wook JeongChang Hoon HaChan Joo LeeHo-Geun YoonPublished in: Proceedings of the National Academy of Sciences of the United States of America (2018)
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.
Keyphrases
- endothelial cells
- nitric oxide
- nitric oxide synthase
- histone deacetylase
- signaling pathway
- wild type
- cell proliferation
- cell death
- high glucose
- cardiovascular disease
- pi k akt
- vascular endothelial growth factor
- hydrogen peroxide
- metabolic syndrome
- heart failure
- induced pluripotent stem cells
- coronary artery
- adipose tissue
- transcription factor
- dna binding
- atomic force microscopy
- weight loss