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Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice

BACKGROUND: Kallistatin exerts beneficial effects on organ injury by inhibiting oxidative stress and inflammation. However, the role of kallistatin in atherosclerosis is largely unknown. Here, we investigated the role and mechanisms of kallistatin in patients with coronary artery disease (CAD), athe...

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Autores principales: Yao, Yuyu, Li, Bing, Liu, Chang, Fu, Cong, Li, Pengfei, Guo, Youming, Ma, Genshan, Liu, Naifeng, Chao, Lee, Chao, Julie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404169/
https://www.ncbi.nlm.nih.gov/pubmed/30554563
http://dx.doi.org/10.1161/JAHA.118.009562
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author Yao, Yuyu
Li, Bing
Liu, Chang
Fu, Cong
Li, Pengfei
Guo, Youming
Ma, Genshan
Liu, Naifeng
Chao, Lee
Chao, Julie
author_facet Yao, Yuyu
Li, Bing
Liu, Chang
Fu, Cong
Li, Pengfei
Guo, Youming
Ma, Genshan
Liu, Naifeng
Chao, Lee
Chao, Julie
author_sort Yao, Yuyu
collection PubMed
description BACKGROUND: Kallistatin exerts beneficial effects on organ injury by inhibiting oxidative stress and inflammation. However, the role of kallistatin in atherosclerosis is largely unknown. Here, we investigated the role and mechanisms of kallistatin in patients with coronary artery disease (CAD), atherosclerotic plaques of apoE(−/−) mice, and endothelial activation. METHODS AND RESULTS: Plasma kallistatin levels were analyzed in 453 patients at different stages of CAD. Kallistatin levels were significantly lower in patients with CAD and negatively associated with CAD severity and oxidative stress. Human kallistatin cDNA in an adenoviral vector was injected intravenously into apoE(−/−) mice after partial carotid ligation, with or without nitric oxide synthase inhibitor (N(ω)‐nitro‐L‐arginine methyl ester) or sirtuin 1 inhibitor (nicotinamide). Kallistatin gene delivery significantly reduced macrophage deposition, oxidative stress, and plaque volume in the carotid artery, compared with control adenoviral injection. Kallistatin administration increased endothelial nitrous oxide synthase, sirtuin 1, interleukin‐10, superoxide dismutase 2, and catalase expression in carotid plaques. The beneficial effects of kallistatin in mice were mitigated by N(ω)‐nitro‐L‐arginine methyl ester or nicotinamide. Furthermore, human kallistatin protein suppressed tumor necrosis factor‐α–induced NADPH oxidase activity and increased endothelial nitrous oxide synthase and sirtuin 1 expression in cultured human endothelial cells. These effects were also abolished by N(ω)‐nitro‐L‐arginine methyl ester or nicotinamide. CONCLUSIONS: This was the first study to demonstrate that reduced plasma kallistatin levels in patients are associated with CAD severity and oxidative stress. Kallistatin treatment prevents carotid atherosclerotic plaque formation in mice by stimulating the sirtuin 1/endothelial nitrous oxide synthase pathway. These findings indicate the potential protective effects of kallistatin on atherosclerosis in human subjects and mouse models.
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spelling pubmed-64041692019-03-18 Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice Yao, Yuyu Li, Bing Liu, Chang Fu, Cong Li, Pengfei Guo, Youming Ma, Genshan Liu, Naifeng Chao, Lee Chao, Julie J Am Heart Assoc Original Research BACKGROUND: Kallistatin exerts beneficial effects on organ injury by inhibiting oxidative stress and inflammation. However, the role of kallistatin in atherosclerosis is largely unknown. Here, we investigated the role and mechanisms of kallistatin in patients with coronary artery disease (CAD), atherosclerotic plaques of apoE(−/−) mice, and endothelial activation. METHODS AND RESULTS: Plasma kallistatin levels were analyzed in 453 patients at different stages of CAD. Kallistatin levels were significantly lower in patients with CAD and negatively associated with CAD severity and oxidative stress. Human kallistatin cDNA in an adenoviral vector was injected intravenously into apoE(−/−) mice after partial carotid ligation, with or without nitric oxide synthase inhibitor (N(ω)‐nitro‐L‐arginine methyl ester) or sirtuin 1 inhibitor (nicotinamide). Kallistatin gene delivery significantly reduced macrophage deposition, oxidative stress, and plaque volume in the carotid artery, compared with control adenoviral injection. Kallistatin administration increased endothelial nitrous oxide synthase, sirtuin 1, interleukin‐10, superoxide dismutase 2, and catalase expression in carotid plaques. The beneficial effects of kallistatin in mice were mitigated by N(ω)‐nitro‐L‐arginine methyl ester or nicotinamide. Furthermore, human kallistatin protein suppressed tumor necrosis factor‐α–induced NADPH oxidase activity and increased endothelial nitrous oxide synthase and sirtuin 1 expression in cultured human endothelial cells. These effects were also abolished by N(ω)‐nitro‐L‐arginine methyl ester or nicotinamide. CONCLUSIONS: This was the first study to demonstrate that reduced plasma kallistatin levels in patients are associated with CAD severity and oxidative stress. Kallistatin treatment prevents carotid atherosclerotic plaque formation in mice by stimulating the sirtuin 1/endothelial nitrous oxide synthase pathway. These findings indicate the potential protective effects of kallistatin on atherosclerosis in human subjects and mouse models. John Wiley and Sons Inc. 2018-11-02 /pmc/articles/PMC6404169/ /pubmed/30554563 http://dx.doi.org/10.1161/JAHA.118.009562 Text en © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Yao, Yuyu
Li, Bing
Liu, Chang
Fu, Cong
Li, Pengfei
Guo, Youming
Ma, Genshan
Liu, Naifeng
Chao, Lee
Chao, Julie
Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
title Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
title_full Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
title_fullStr Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
title_full_unstemmed Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
title_short Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice
title_sort reduced plasma kallistatin is associated with the severity of coronary artery disease, and kallistatin treatment attenuates atherosclerotic plaque formation in mice
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404169/
https://www.ncbi.nlm.nih.gov/pubmed/30554563
http://dx.doi.org/10.1161/JAHA.118.009562
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