Homocysteine facilitates LOX-1 activation and endothelial death through the PKCβ and SIRT1/HSF1 mechanism: relevance to human hyperhomocysteinaemia
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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LOX-1 up-regulation by hyperhomocysteinemia prompts reactive oxygen species formation, induces pro-apoptotic signal transduction and nitric oxide catabolism, and consequently causes oxidative injury and endothelial cell death.
“which prompts reactive oxygen species (ROS) formation,8, 9 induces pro‐apoptotic signal transduction and nitric oxide (NO) catabolism, consequently causing oxidative injury and the endothelial cells death.10, 11”
From Picroside <scp>II</scp> attenuates hyperhomocysteinemia‐induced endothelial injury by reducing inflammation, oxidative stress and cell apoptosis (2019) · cites this paper as [8]
Hyperhomocysteinemia up-regulates LOX-1 expression in human mononuclear and endothelial cells.
“Much studies have shown that HHcy up‐regulated human mononuclear and endothelial cells LOX‐1 expression,7, 8”
From Picroside <scp>II</scp> attenuates hyperhomocysteinemia‐induced endothelial injury by reducing inflammation, oxidative stress and cell apoptosis (2019) · cites this paper as [8]
SIRT1 decreases LOX-1 expression and NF-κB activation.
“and SIRT1 decreased the LOX‐1 expression level and NF‐κB activation.8, 25”
From Picroside <scp>II</scp> attenuates hyperhomocysteinemia‐induced endothelial injury by reducing inflammation, oxidative stress and cell apoptosis (2019) · cites this paper as [8]
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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
- Publisher
- Portland Press Ltd.
- 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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