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Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet

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. T...

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Autores principales: Zhang, Meng, Zhao, Hongting, Cai, Jing, Li, Huihui, Wu, Qi, Qiao, Tong, Li, Kuanyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621700/
https://www.ncbi.nlm.nih.gov/pubmed/28961281
http://dx.doi.org/10.1371/journal.pone.0185688
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author Zhang, Meng
Zhao, Hongting
Cai, Jing
Li, Huihui
Wu, Qi
Qiao, Tong
Li, Kuanyu
author_facet Zhang, Meng
Zhao, Hongting
Cai, Jing
Li, Huihui
Wu, Qi
Qiao, Tong
Li, Kuanyu
author_sort Zhang, Meng
collection PubMed
description 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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spelling pubmed-56217002017-10-17 Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet Zhang, Meng Zhao, Hongting Cai, Jing Li, Huihui Wu, Qi Qiao, Tong Li, Kuanyu PLoS One Research Article 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. Public Library of Science 2017-09-29 /pmc/articles/PMC5621700/ /pubmed/28961281 http://dx.doi.org/10.1371/journal.pone.0185688 Text en © 2017 Zhang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Zhang, Meng
Zhao, Hongting
Cai, Jing
Li, Huihui
Wu, Qi
Qiao, Tong
Li, Kuanyu
Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet
title Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet
title_full Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet
title_fullStr Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet
title_full_unstemmed Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet
title_short Chronic administration of mitochondrion-targeted peptide SS-31 prevents atherosclerotic development in ApoE knockout mice fed Western diet
title_sort chronic administration of mitochondrion-targeted peptide ss-31 prevents atherosclerotic development in apoe knockout mice fed western diet
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621700/
https://www.ncbi.nlm.nih.gov/pubmed/28961281
http://dx.doi.org/10.1371/journal.pone.0185688
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