title: 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.
authors.affiliation: Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ching-Hsia
authors.initials: CH
authors.lastname: Hung
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shih-Hung
authors.initials: SH
authors.lastname: Chan
authors.affiliation: Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Pei-Ming
authors.initials: PM
authors.lastname: Chu
authors.affiliation: Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan kunlingtsai@mail.ncku.edu.tw.
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Tsai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D000076249:Heat Shock Transcription Factors; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; C495138:Olr1 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D014157:Transcription Factors; D006710:Homocysteine; D008715:Methionine; D019255:NADPH Oxidases; D064546:Protein Kinase C beta; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: heat-shock transcription factor 1; hyperhomocysteinaemia; lectin-like oxidized low-density lipoprotein receptor 1; protein kinase C; sirtuin 1