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Pharmacological inhibition of endothelial HDAC6 provides protection against atherogenesis through upregulation of cystathionine gamma‐lyase derived hydrogen sulfide
Author(s) -
Leucker Thorsten Martin,
Kim Jae Hyung,
Nomura Yohei,
Bhatta Anil,
Wang Victor,
Pandey Deepesh
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1065.14
Subject(s) - cystathionine gamma lyase , hdac6 , downregulation and upregulation , endothelium , gene knockdown , endothelial dysfunction , microbiology and biotechnology , endothelial stem cell , chemistry , cystathionine beta synthase , cancer research , medicine , immunology , biology , pharmacology , histone , endocrinology , biochemistry , enzyme , gene , in vitro , histone deacetylase , cysteine
Endothelial cystathionine gamma‐lyase (CSE) molecular mechanisms that control CSE gene expression in vascular endothelium during cardiovascular diseases are unclear. In this study, isolated murine aortic rings exposed to OxLDL (50mg/ml) for 24 hours exhibited impaired endothelial‐dependent vascular relaxation but were protected by adenoviral‐mediated increases in CSE expression. Cultured human aortic endothelial cells (HAECs) that were exposed to OxLDL and intact aortas from atherogenic ApoE knockout mice fed a high‐fat diet for 12 weeks both exhibited reduced CSE mRNA and protein expression. Utilizing class‐specific inhibitors of histone deacetylases (HDACs) class‐specific inhibitors and HDAC6 specific small molecule inhibitor and siRNA, we identified HDAC6 to be a critical regulator of endothelial CSE expression in response to injury stimulus such as OxLDL. HDAC6 mRNA and protein expression were both upregulated in OxLDL exposed HAECs. The reduced endothelial CSE expression/activity with OxLDL was reversed by an HDAC6 inhibitor, tubacin (10mM), and by HDAC6 siRNA (30nM). Further, OxLDL significantly impaired endothelial‐dependent vascular relaxation in mouse aortic rings and reduced CSE expression. The deleterious effect of OxLDL was significantly improved by adenoviral‐mediated overexpression of CSE in murine aortas and by inhibition of HDAC6 with tubacin. Our findings show that HDAC6 is a critical regulator of CSE expression in the vascular endothelium, and strategies to inhibit HDAC6 activity may improve endothelial function and prevent/reverse the development of atherosclerosis. Support or Funding Information This work was supported by American Heart Association Scientist Development Grant to D. Pandey (16SDG27340010), 2017 StAAR award from Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine to D. Pandey and National Institutes of Health‐National Heart, Lung, and Blood Institute training grant T32‐HL007227‐40 to T. Leucker.