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), ather...
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-11-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.118.009562 |
| _version_ | 1811334155420565504 |
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| author | Yuyu Yao Bing Li Chang Liu Cong Fu Pengfei Li Youming Guo Genshan Ma Naifeng Liu Lee Chao Julie Chao |
| author_facet | Yuyu Yao Bing Li Chang Liu Cong Fu Pengfei Li Youming Guo Genshan Ma Naifeng Liu Lee Chao Julie Chao |
| author_sort | Yuyu Yao |
| collection | DOAJ |
| 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 (Nω‐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 Nω‐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 Nω‐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. |
| first_indexed | 2024-04-13T17:03:38Z |
| format | Article |
| id | doaj.art-c884a32985a44b89a9bb06829beef100 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T17:03:38Z |
| publishDate | 2018-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-c884a32985a44b89a9bb06829beef1002022-12-22T02:38:34ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802018-11-0172110.1161/JAHA.118.009562Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in MiceYuyu Yao0Bing Li1Chang Liu2Cong Fu3Pengfei Li4Youming Guo5Genshan Ma6Naifeng Liu7Lee Chao8Julie Chao9Department of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing ChinaDepartment of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing ChinaDepartment of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing ChinaDepartment of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing ChinaDepartment of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SCDepartment of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SCDepartment of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing ChinaDepartment of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing ChinaDepartment of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SCDepartment of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SCBackground 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 (Nω‐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 Nω‐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 Nω‐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.https://www.ahajournals.org/doi/10.1161/JAHA.118.009562atherosclerosiscoronary artery diseasekallistatinoxidative stresssirtuin 1 |
| spellingShingle | Yuyu Yao Bing Li Chang Liu Cong Fu Pengfei Li Youming Guo Genshan Ma Naifeng Liu Lee Chao Julie Chao Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atherosclerosis coronary artery disease kallistatin oxidative stress sirtuin 1 |
| 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 | atherosclerosis coronary artery disease kallistatin oxidative stress sirtuin 1 |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.118.009562 |
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