Zhou Ji, Werstuck Geoff H, Lhoták Sárka, de Koning A B Lawrence, Sood Sudesh K, Hossain Gazi S, Møller Jan, Ritskes-Hoitinga Merel, Falk Erling, Dayal Sanjana, Lentz Steven R, Austin Richard C
Henderson Research Centre and McMaster University, Hamilton, Ontario, Canada.
Circulation. 2004 Jul 13;110(2):207-13. doi: 10.1161/01.CIR.0000134487.51510.97. Epub 2004 Jun 21.
A causal relation between hyperhomocysteinemia (HHcy) and accelerated atherosclerosis has been established in apolipoprotein E-deficient (apoE-/-) mice. Although several cellular stress mechanisms have been proposed to explain the atherogenic effects of HHcy, including oxidative stress, endoplasmic reticulum (ER) stress, and inflammation, their association with atherogenesis has not been completely elucidated.
ApoE-/- mice were fed a control or a high-methionine (HM) diet for 4 (early lesion group) or 18 (advanced lesion group) weeks to induce HHcy. Total plasma homocysteine levels and atherosclerotic lesion size were significantly increased in early and advanced lesion groups fed the HM diet compared with control groups. Markers of ER stress (GRP78/94, phospho-PERK), oxidative stress (HSP70), and inflammation (phospho-IkappaB-alpha) were assessed by immunohistochemical staining of these atherosclerotic lesions. GRP78/94, HSP70, and phospho-IkappaB-alpha immunostaining were significantly increased in the advanced lesion group fed the HM diet compared with the control group. HSP47, an ER-resident molecular chaperone involved in collagen folding and secretion, was also increased in advanced lesions of mice fed the HM diet. GRP78/94 and HSP47 were predominantly localized to the smooth muscle cell-rich fibrous cap, whereas HSP70 and phospho-IkappaB-alpha were observed in the lipid-rich necrotic core. Increased HSP70 and phospho-IkappaB-alpha immunostaining in advanced lesions of mice fed the HM diet are consistent with enhanced carotid artery dihydroethidium staining. Interestingly, GRP78/94 and phospho-PERK were markedly increased in macrophage foam cells from early lesions of mice fed the control or the HM diet.
Multiple cellular stress pathways, including ER stress, are associated with atherosclerotic lesion development in apoE-/- mice.
在载脂蛋白E缺陷（apoE-/-）小鼠中，高同型半胱氨酸血症（HHcy）与动脉粥样硬化加速之间的因果关系已得到证实。尽管已经提出了几种细胞应激机制来解释HHcy的致动脉粥样硬化作用，包括氧化应激、内质网（ER）应激和炎症，但其与动脉粥样硬化发生的关联尚未完全阐明。
给apoE-/-小鼠喂食对照饮食或高蛋氨酸（HM）饮食4周（早期病变组）或18周（晚期病变组）以诱导HHcy。与对照组相比，喂食HM饮食的早期和晚期病变组的总血浆同型半胱氨酸水平和动脉粥样硬化病变大小显著增加。通过对这些动脉粥样硬化病变进行免疫组织化学染色来评估ER应激（GRP78/94、磷酸化PERK）、氧化应激（HSP70）和炎症（磷酸化IκB-α）的标志物。与对照组相比，喂食HM饮食的晚期病变组中GRP78/94、HSP70和磷酸化IκB-α免疫染色显著增加。HSP47是一种参与胶原蛋白折叠和分泌的内质网驻留分子伴侣，在喂食HM饮食的小鼠晚期病变中也增加。GRP78/94和HSP47主要定位于富含平滑肌细胞的纤维帽，而HSP70和磷酸化IκB-α在富含脂质的坏死核心中观察到。喂食HM饮食的小鼠晚期病变中HSP70和磷酸化IκB-α免疫染色增加与颈动脉二氢乙锭染色增强一致。有趣的是，在喂食对照饮食或HM饮食的小鼠早期病变的巨噬细胞泡沫细胞中，GRP78/94和磷酸化PERK显著增加。
包括ER应激在内的多种细胞应激途径与apoE-/-小鼠的动脉粥样硬化病变发展相关。
