A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory ResponsesReportar como inadecuado




A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Herp was originally identified as an endoplasmic reticulum ER stress protein in vascular endothelial cells. ER stress is induced in atherosclerotic lesions, but it is not known whether Herp plays any role in the development of atherosclerosis. To address this question, we generated Herp- and apolipoprotein E apoE-deficient mice Herp−-−; apoE−-− mice by crossbreeding Herp−-− mice and apoE−-− mice. Herp was expressed in the endothelial cells and medial smooth muscle cells of the aorta, as well as in a subset of macrophages in the atherosclerotic lesions in apoE−-− mice, while there was no expression of Herp in the Herp−-−; apoE−-− mice. The doubly deficient mice developed significantly fewer atherosclerotic lesions than the apoE−-− mice at 36 and 72 weeks of age, whereas the plasma levels of cholesterol and triglycerides were not significantly different between the strains. The plasma levels of non-esterified fatty acids were significantly lower in the Herp−-−; apoE−-− mice when they were eight and 16 weeks old. The gene expression levels of ER stress response proteins GRP78 and CHOP and inflammatory cytokines IL-1β, IL-6, TNF-α and MCP-1 in the aorta were significantly lower in Herp−-−; apoE−-− mice than in apoE−-− mice, suggesting that Herp mediated ER stress-induced inflammation. In fact, peritoneal macrophages isolated from Herp-deficient mice and RAW264.7 macrophages in which Herp was eliminated with a siRNA expressed lower levels of mRNA for inflammatory cytokines when they were treated with tunicamycin. Herp deficiency affected the major mediators of the unfolded protein response, including IRE1 and PERK, but not ATF6. These findings suggest that a deficiency of Herp suppressed the development of atherosclerosis by attenuating the ER stress-induced inflammatory reactions.



Autor: Shohei Shinozaki, Tsuyoshi Chiba, Koichi Kokame, Toshiyuki Miyata, Eiji Kaneko, Kentaro Shimokado

Fuente: http://plos.srce.hr/



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