Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet.
Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet.
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长期给予线粒体靶向肽 SS-31 可预防喂食西方饮食的 ApoE 基因敲除小鼠的动脉粥样硬化发展
DOI：
10.1371/journal.pone.0185688
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Li K
中科院分区：
文献类型：
--
作者：
Zhang M;Zhao H;Cai J;Li H;Wu Q;Qiao T;Li K
背景氧化应激和炎症因子与动脉粥样硬化的进展密切相关。据报道，线粒体靶向肽 SS-31 选择性靶向与心磷脂反应的线粒体内膜，可抑制 ROS 生成并减轻炎症。本研究旨在研究 SS-31 是否可以抑制体内动脉粥样硬化的发展。方法雄性ApoE-/-小鼠（8周龄）西式饮食喂养，皮下注射生理盐水或SS-31（1 mg/kg/d或3 mg/kg/d），连续12周。进行油红O染色以评估斑块的面积和大小。对 8-OHDG 进行 DHE 染色和免疫组织化学染色以评估氧化应激。通过ATP生物发光检测试剂盒评估主动脉ATP含量。通过CD68和α-SMA的免疫组织化学染色以及Masson三色染色来评估动脉粥样硬化斑块的成分。进行生化测定以确定超氧化物歧化酶（SOD）的蛋白质水平和活性。通过免疫组织化学和生化方法测定 CD36、LOX-1 和 ABCA1 的水平，以评估主动脉和腹膜巨噬细胞中的胆固醇转运。采用ELISA法检测血清中ICAM-1、MCP-1、IL-6、CRP等炎症因子。结果 SS-31 给药减少了 ApoE-/- 小鼠中西方饮食诱导的动脉粥样硬化斑块的面积和大小，并改变了斑块的成分。长期施用 SS-31 后，氧化应激受到抑制，DHE 染色减少、8-OHDG 表达下调、SOD 活性增加。此外，通过降低血清 ICAM-1、MCP-1 和 IL-6 水平可以看出，全身炎症得到改善。最重要的是，SS-31 给药通过下调 CD36 和 LOX-1 的表达来抑制胆固醇流入，以防止脂质积累，从而进一步抑制泡沫细胞形成和动脉粥样硬化进展。结论 SS-31 可以预防 ApoE-/- 小鼠中动脉粥样硬化的形成，表明 SS-31 可能被认为是预防动脉粥样硬化进展的潜在药物。
Background Oxidative stress and inflammatory factors are deeply involved in progression of atherosclerosis. Mitochondrion-targeted peptide SS-31, selectively targeting to mitochondrial inner membrane reacting with cardiolipin, has been reported to inhibit ROS generation and mitigate inflammation. The present study was designed to investigate whether SS-31 could suppress the development of atherosclerosis in vivo. Methods Male ApoE-/- mice (8 weeks old) fed with Western diet were treated with normal saline or SS-31 (1 mg/kg/d or 3 mg/kg/d) through subcutaneous injection for 12 weeks. Oil Red O staining was performed to evaluate area and sizes of the plaques. DHE staining and immunohistochemical staining of 8-OHDG was performed to assess the oxidative stress. The aorta ATP contents were assessed by the ATP bioluminescence assay kit. Immunohistochemical staining of CD68 and α-SMA and Masson’s trichrome staining were performed to evaluate the composition of atherosclerotic plaque. Biochemical assays were performed to determine the protein level and activity of superoxide dismutase (SOD). The levels of CD36, LOX-1 and ABCA1 were immunohistochemically and biochemically determined to evaluate the cholesterol transport in aorta and peritoneal macrophages. Inflammatory factors, including ICAM-1, MCP-1, IL-6 and CRP in serum, were detected through ELISA. Results SS-31 administration reduced the area and sizes of western diet-induced atherosclerotic plaques and changed the composition of the plaques in ApoE-/- mice. Oxidative stress was suppressed, as evidenced by the reduced DHE stain, down-regulated 8-OHDG expression, and increased SOD activity after chronic SS-31 administration. Moreover, systemic inflammation was ameliorated as seen by decreasing serum ICAM-1, MCP-1, and IL-6 levels. Most importantly, SS-31 administration inhibited cholesterol influx by down-regulating expression of CD36 and LOX-1 to prevent lipid accumulation to further suppress the foam cell formation and atherosclerotic progression. Conclusion Administration of SS-31 prevents against atherosclerotic formation in ApoE-/- mice suggesting that SS-31 might be considered to be a potential drug to prevent atherosclerotic progression.
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DOI：
10.1038/nri3520
发表时间：
2013-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
20.1
作者：
Mehta, Jawahar L.;Sanada, Nobuhito;Sawamura, Tatsuya
通讯作者：
Sawamura, Tatsuya
影响因子：
15.9
作者：
Anderson, Ethan J.;Lustig, Mary E.;Neufer, P. Darrell
通讯作者：
Neufer, P. Darrell
影响因子：
37.8
作者：
Higashi Y;Sukhanov S;Shai SY;Danchuk S;Tang R;Snarski P;Li Z;Lobelle-Rich P;Wang M;Wang D;Yu H;Korthuis R;Delafontaine P
通讯作者：
Delafontaine P
影响因子：
5
作者：
Rios-Navarro, Cesar;de Pablo, Carmen;Alvarez, Angeles
通讯作者：
Alvarez, Angeles