Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium

Seung Hyun Lee, Jaesung Seo, Soo Yeon Park, Mi Hyeon Jeong, Hyo Kyoung Choi, Chan Joo Lee, Mi Jeong Kim, Garam Guk, Soo Yeon Lee, Hyewon Park, Jae Wook Jeong, Chang Hoon Ha, Sungha Park, Ho Geun Yoon

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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.

Original languageEnglish
Pages (from-to)4672-4677
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number18
DOIs
Publication statusPublished - 2018 May 1

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Cytoprotection
Endothelium
Cell Death
Nitric Oxide Synthase Type III
Atherosclerosis
Nitric Oxide
Proto-Oncogene Proteins c-akt
Human Umbilical Vein Endothelial Cells
Knockout Mice
HDL Cholesterol
Ligation
Signal Transduction
Diabetes Mellitus
Phosphorylation
Calcium

All Science Journal Classification (ASJC) codes

  • General

Cite this

Lee, Seung Hyun ; Seo, Jaesung ; Park, Soo Yeon ; Jeong, Mi Hyeon ; Choi, Hyo Kyoung ; Lee, Chan Joo ; Kim, Mi Jeong ; Guk, Garam ; Lee, Soo Yeon ; Park, Hyewon ; Jeong, Jae Wook ; Ha, Chang Hoon ; Park, Sungha ; Yoon, Ho Geun. / Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 18. pp. 4672-4677.
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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.",
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Lee, SH, Seo, J, Park, SY, Jeong, MH, Choi, HK, Lee, CJ, Kim, MJ, Guk, G, Lee, SY, Park, H, Jeong, JW, Ha, CH, Park, S & Yoon, HG 2018, 'Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 18, pp. 4672-4677. https://doi.org/10.1073/pnas.1712918115

Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium. / Lee, Seung Hyun; Seo, Jaesung; Park, Soo Yeon; Jeong, Mi Hyeon; Choi, Hyo Kyoung; Lee, Chan Joo; Kim, Mi Jeong; Guk, Garam; Lee, Soo Yeon; Park, Hyewon; Jeong, Jae Wook; Ha, Chang Hoon; Park, Sungha; Yoon, Ho Geun.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 18, 01.05.2018, p. 4672-4677.

Research output: Contribution to journalArticle

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T1 - Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium

AU - Lee, Seung Hyun

AU - Seo, Jaesung

AU - Park, Soo Yeon

AU - Jeong, Mi Hyeon

AU - Choi, Hyo Kyoung

AU - Lee, Chan Joo

AU - Kim, Mi Jeong

AU - Guk, Garam

AU - Lee, Soo Yeon

AU - Park, Hyewon

AU - Jeong, Jae Wook

AU - Ha, Chang Hoon

AU - Park, Sungha

AU - Yoon, Ho Geun

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

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U2 - 10.1073/pnas.1712918115

DO - 10.1073/pnas.1712918115

M3 - Article

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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