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.
Homocysteine facilitates LOX-1 activation and endothelial death through the PKCβ and SIRT1/HSF1 mechanism: relevance to human hyperhomocysteinaemia
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Ching-Hsia Hung, Shih-Hung Chan, Pei-Ming Chu, Kun-Ling Tsai; Homocysteine facilitates LOX-1 activation and endothelial death through the PKCβ and SIRT1/HSF1 mechanism: relevance to human hyperhomocysteinaemia. Clin Sci (Lond) 1 September 2015; 129 (6): 477–487. doi: https://doi.org/10.1042/CS20150127
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