摘要：
Objective Chronic stress is an important risk factor for atherosclerotic diseases. Our previous studies have shown that chronic unpredictable mild stress (CUMS) accelerates atherosclerosis and up-regulates TLR4/NF-kappa B expression in apoE(-/-) mice. However, TLR4/NF-kappa B signaling whether directly contributes to the development of atherosclerosis in CUMS mice is unclear. We hypothesized that the interference of TLR4/NF-kappa B can ameliorate CUMS-induced inflammation and atherosclerosis in apoE(-/-) mice. Methods ApoE(-/-) mice were exposed to 12 weeks CUMS. Ad-siRNA TLR4 was given by tail vein injection (10 mu l/mouse, every 5 days), and PDTC (an inhibitor of NF-kappa B) was given by intraperitoneal injection (60 mg/kg, once a day). Plasma corticosterone concentrations were determined by solid-phase I-125 radioimmunoassay. Atherosclerosis lesions in aortic sinuses were evaluated and quantified by IMAGEPRO PLUS. Western blotting was used to detect the expression of TLR4, NF-kappa B, and IL-1 beta in aortas of the mice. Plasma lipid profiles, IL-1 beta, TNF-alpha, and MCP-1 were measured by ELISA. Results Our results indicated that CUMS apoE(-/-) mice treatment with siRNA TLR4 significantly decreased atherosclerosis and down-regulated TLR4, NF-kappa B, and inflammatory cytokines. PDTC also remarkably reduced atherosclerosis and the levels of IL-1 beta, TNF-alpha and MCP-1 in plasma. However, Treatment with siRNA TLR4 or PDTC had no effect on plasma corticosterone levels, and lipid profiles. Conclusions TLR4/NF-kappa B pathway may participate in CUMS-induced atherosclerosis through activation of proinflammatory cytokines in apoE(-/-) mice. Our data may provide a new potential therapeutic target for prevention of CUMS-induced atherosclerosis.
作者机构：
[Gu Hong-Feng] Univ South China, Dept Physiol, Hengyang 421001, Peoples R China.;[Gu Hong-Feng; Yang Yong-Zong] Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Peoples R China.;[Jiang Jian-Hong] Nanhua Univ, Chuanshan Coll, Hengyang 421001, Peoples R China.;[Tong Qiao-Zhen; Liao Duan-Fang] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Gu Hong-Feng] U;Univ South China, Dept Physiol, Hengyang 421001, Peoples R China.
关键词：
GP Ⅱb/Ⅲa;atherosclerosis;HMGB-1;TLR4;NF-κB
摘要：
The effects of glycoprotein (GP) Ⅱb/Ⅲa inhibitors on the development of the atherosclerotic process has received scant attention. To investigate whether GP Ⅱb/Ⅲa blockade influences atherosclerosis lesion and HMGB-1/TLR4 signaling, we compared plaque formation in ApoE~(-/-) mice: control group (n=10); IgG group (n=10, 50 μg) and GP Ⅱb/Ⅲa mAb group (n=10, 50 μg). All mice were fed on a Western diet (10% fat and 1.25% cholesterol) for 10 weeks. GP Ⅱb/Ⅲa blockade significantly decreased the atherosclerotic lesion and platelet adhesion to the vessel wall. Immunohistochemistry analysis showed that blocking GP Ⅱb/Ⅲa diminished MOMA-2 and VCAM-1 expression in aortic plaque in ApoE~(-/-) mice. Western blot results indicated that HMGB-1, TLR4, and NF-κB levels were markedly reduced in arteries of ApoE-/- mice treated with GP Ⅱb/Ⅲa mAb (P < 0.05). Moreover, GP Ⅱb/Ⅲa mAb decreased plasma HMGB-1, IL-1β, TNF-α and MCP-1 concentrations. Our findings demonstrated that GP Ⅱb/Ⅲa mAb significantly decreased atherosclerotic lesions and HMGB-1, TLR4 and NF-κB expression in ApoE~(-/-) mice (P < 0.05). The present study has suggested a possibility that GP Ⅱb/Ⅲa blockade attenuates atherosclerosis by inhibiting the HMGB-1/TLR4 pathway..
