Histone and DNA Methylation–Mediated Epigenetic Downregulation of Endothelial Kruppel-Like Factor 2 by Low-Density Lipoprotein Cholesterol

Ajay Kumar; Santosh Kumar; Ajit Vikram; Timothy A Hoffman; Asma Naqvi; Christopher M Lewarchik; Young-Rae Kim; Kaikobad Irani

doi:10.1161/ATVBAHA.113.301765

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Histone and DNA Methylation–Mediated Epigenetic Downregulation of Endothelial Kruppel-Like Factor 2 by Low-Density Lipoprotein Cholesterol

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Histone and DNA Methylation–Mediated Epigenetic Downregulation of Endothelial Kruppel-Like Factor 2 by Low-Density Lipoprotein Cholesterol

Ajay Kumar, Santosh Kumar, Ajit Vikram, Timothy A Hoffman, Asma Naqvi, Christopher M Lewarchik, Young-Rae Kim and Kaikobad Irani

Arteriosclerosis, thrombosis, and vascular biology, Vol.33(8), pp.1936-1942

08/2013

DOI: 10.1161/ATVBAHA.113.301765

PMID: 23723375

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Abstract

Objective: Low-density lipoprotein (LDL) cholesterol induces endothelial dysfunction and is a major modifiable risk factor for coronary heart disease. Endothelial Kruppel-like Factor 2 (KLF2) is a transcription factor that is vital to endothelium-dependent vascular homeostasis. The purpose of this study is to determine whether and how LDL affects endothelial KLF2 expression. Approach and results: LDL downregulates KLF2 expression and promoter activity in endothelial cells. LDL-induced decrease in KLF2 parallels changes in endothelial KLF2 target genes thrombomodulin, endothelial NO synthase, and plasminogen activator inhibitor-1. Pharmacological inhibition of DNA methyltransferases or knockdown of DNA methyltransferase 1 prevents downregulation of endothelial KLF2 by LDL. LDL induces endothelial DNA methyltransferase 1 expression and DNA methyltransferase activity. LDL stimulates binding of the DNA methyl-CpG-binding protein-2 and histone methyltransferase enhancer of zeste homolog 2, whereas decreases binding of the KLF2 transcriptional activator myocyte enhancing factor-2, to the KLF2 promoter in endothelial cells. Knockdown of myocyte enhancing factor-2, or mutation of the myocyte enhancing factor-2 site in the KLF2 promoter, abrogates LDL-induced downregulation of endothelial KLF2 and thrombomodulin, and KLF2 promoter activity. Similarly, knockdown of enhancer of zeste homolog 2 negates LDL-induced downregulation of KLF2 and thrombomodulin in endothelial cells. Finally, overexpression of KLF2 rescues LDL-induced clotting of platelet-rich plasma on endothelial cells. Conclusions: LDL represses endothelial KLF2 expression via DNA and histone methylation. Downregulation of KLF2 by LDL leads to a dysfunctional, hypercoagulable endothelium.

Details

Title: Subtitle: Histone and DNA Methylation–Mediated Epigenetic Downregulation of Endothelial Kruppel-Like Factor 2 by Low-Density Lipoprotein Cholesterol
Creators: Ajay Kumar - From the Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. K.I. is currently affiliated with the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
Santosh Kumar - From the Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. K.I. is currently affiliated with the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
Ajit Vikram - From the Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. K.I. is currently affiliated with the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
Timothy A Hoffman - From the Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. K.I. is currently affiliated with the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
Asma Naqvi - From the Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. K.I. is currently affiliated with the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
Christopher M Lewarchik - From the Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. K.I. is currently affiliated with the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
Young-Rae Kim - From the Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. K.I. is currently affiliated with the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
Kaikobad Irani - From the Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. K.I. is currently affiliated with the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.33(8), pp.1936-1942
DOI: 10.1161/ATVBAHA.113.301765
PMID: 23723375
NLM abbreviation: Arterioscler Thromb Vasc Biol
ISSN: 1079-5642
eISSN: 1524-4636
Language: English
Date published: 08/2013
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984046907002771

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