Cited by 26Folate and B Vitamins ResearchNitric Oxide and Endothelin EffectsAtherosclerosis and Cardiovascular Diseases

Homocysteine facilitates LOX-1 activation and endothelial death through the PKCβ and SIRT1/HSF1 mechanism: relevance to human hyperhomocysteinaemia

Hung, Ching-Hsia, Chan, Shih-Hung, Chu, Pei-Ming, Tsai, Kun-Ling·2015·Clinical Science

Abstract

HHcy (hyperhomocysteinaemia) is one of the major risk factors for cardiovascular diseases. A high concentration of Hcy (homocysteine) induces endothelial dysfunction by activating endothelial oxidative stress. LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1) plays a vital role in regulating the progression of atherosclerotic lesions. LOX-1 activation causes endothelial apoptosis and inflammation. The mechanism is still unclear as to whether Hcy affects human endothelial LOX-1 expression. LOX-1 expression level was confirmed by Western blotting assay in Hcy-treated endothelial cells. L-Methionine was used for HHcy induction in animals. Our results suggested that Hcy increased PKCβ (protein kinase Cβ) activation to enhance the LOX-1 expression level. The up-regulation of PKCβ phosphorylation subsequently causes ROS (reactive oxygen species) formation and SIRT1 (sirtuin 1) degradation through a proteasome-dependent mechanism, thereby mitigating the activity of SIRT1 by deacetylating HSF1 (heat-shock transcription factor 1). We also found that NOX2 is a key NAPDH oxidase isoform responsible for the Hcy-caused ROS formation. The overexpression of SIRT1 and HSF1 reduced the Hcy-induced LOX-1 activation. Silencing PKCβ function also reduced LOX-1 activation and endothelial apoptosis caused by Hcy. Our hypothesis was supported by analysing the data from methionine-induced HHcy-affected animals. Our data indicate a new direction for LOX-1 regulation by the modulation of the PKCβ/NAPDH oxidase/SIRT1/HSF1 mechanism. Our findings might provide a novel route for developing new therapeutic treatments for HHcy.

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Crossref · 10.1042/cs20150127

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Authors
Hung, C.-H., Chan, S.-H., Chu, P.-M., & Tsai, K.-L.
Affiliations
  • National Cheng Kung University (TW)
  • National Cheng Kung University Hospital (TW)
  • China Medical University (TW)
Corresponding author
Tsai, Kun-Ling
Venue
Clinical Science
Published
2015-06-22
Volume
129
Issue
6
Pages
477-487
ISSN
  • 0143-5221 (ISSN-L)
  • 1470-8736
OpenAlex
W2279841845
Cited by
25
References
41
Citations by year
2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 2 · 2016: 4
FWCI
3.08
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Science (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
homocysteine, hyperhomocysteinemia, LOX-1, lectin-like oxidized LDL receptor, protein kinase C beta, SIRT1, heat shock factor 1, reactive oxygen species, NOX2, endothelial cell apoptosis, endothelial dysfunction, oxidative stress, atherosclerosis, methionine-induced hyperhomocysteinemia, proteasomal degradation
MeSH terms
Heat Shock Transcription Factors, Animals, Binding Sites, Cells, Cultured, DNA-Binding Proteins, Enzyme Activation, Homocysteine, Humans, Lipoproteins, LDL, Methionine, Mice, Inbred C57BL, Phosphorylation, Protein Processing, Post-Translational, RNA, Messenger, Transcription Factors, Up-Regulation, Apoptosis, Reactive Oxygen Species, NADPH Oxidases, Hyperhomocysteinemia, Endothelial Cells, Scavenger Receptors, Class E, Mice, Sirtuin 1, Protein Kinase C beta

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