Regression of Atherosclerosis in ApoE−/− Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel “Cytotopic” Anti‐Thrombin Without Prolonged Anticoagulation
Background Anticoagulants induce atherosclerosis regression in animal models but exploiting this clinically is limited by bleeding events. Here we test a novel thrombin inhibitor, PTL060, comprising hirulog covalently linked to a synthetic myristoyl electrostatic switch to tether to cell membranes....
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-07-01
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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.119.014811 |
| _version_ | 1818314913640087552 |
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| author | Daxin Chen Ke Li Sam Festenstein Julieta Karegli Hannah Wilkinson Hugh Leonard Lin‐Lin Wei Ning Ma Min Xia Henry Tam Jian‐an Wang Qingbo Xu John H. McVey Richard A. G. Smith Anthony Dorling |
| author_facet | Daxin Chen Ke Li Sam Festenstein Julieta Karegli Hannah Wilkinson Hugh Leonard Lin‐Lin Wei Ning Ma Min Xia Henry Tam Jian‐an Wang Qingbo Xu John H. McVey Richard A. G. Smith Anthony Dorling |
| author_sort | Daxin Chen |
| collection | DOAJ |
| description | Background Anticoagulants induce atherosclerosis regression in animal models but exploiting this clinically is limited by bleeding events. Here we test a novel thrombin inhibitor, PTL060, comprising hirulog covalently linked to a synthetic myristoyl electrostatic switch to tether to cell membranes. Methods and Results ApoE−/− mice were fed chow or high‐fat diets, before transplantation of congenic aortic segments or injection of PTL060, parental hirulog, control saline, or labeled CD11b positive cells. Aortic transplants from transgenic mice expressing anticoagulants on endothelium did not develop atherosclerosis. A single intravenous injection of PTL060, but not hirulog inhibited atheroma development by >50% compared with controls when assessed 4 weeks later. Mice had prolonged bleeding times for only one seventh of the time that PTL060 was biologically active. Repeated weekly injections of PTL060 but not hirulog caused regression of atheroma. We dissected 2 contributory mechanisms. First, the majority of CCR2+ (C‐C chemokine receptor type 2+) monocytes recruited into plaques expressed CCR7 (C‐C chemokine receptor type 7), ABCA1 (ATP‐binding cassette transporter – 1), and interleukin‐10 in PTL060 mice, a phenotype seen in <20% of CCR2+ recruits in controls. Second, after several doses, there was a significant reduction in monocyte recruits, the majority of which were CCR2‐negative with a similar regression‐associated phenotype. Regression equivalent to that induced by intravenous PTL060 was induced by adoptive transfer of CD11b+ cells pre‐coated with PTL060. Conclusions Covalent linkage of a myristoyl electrostatic switch onto hirulog in PTL060 uncouples the pharmacodynamic effects on hemostasis and atherosclerosis, such that plaque regression, mediated predominantly via effects on monocytes, is accompanied by only transient anticoagulation. |
| first_indexed | 2024-12-13T08:57:12Z |
| format | Article |
| id | doaj.art-14b724396b3444ca97b1931d9032ba68 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-13T08:57:12Z |
| publishDate | 2020-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-14b724396b3444ca97b1931d9032ba682022-12-21T23:53:14ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-07-0191310.1161/JAHA.119.014811Regression of Atherosclerosis in ApoE−/− Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel “Cytotopic” Anti‐Thrombin Without Prolonged AnticoagulationDaxin Chen0Ke Li1Sam Festenstein2Julieta Karegli3Hannah Wilkinson4Hugh Leonard5Lin‐Lin Wei6Ning Ma7Min Xia8Henry Tam9Jian‐an Wang10Qingbo Xu11John H. McVey12Richard A. G. Smith13Anthony Dorling14Department of Inflammation Biology School of Immunology and Microbial Sciences King’s College London, Guy’s Hospital London United KingdomCore Research Laboratory the Second Affiliated Hospital, School of Medicine Jiaotong University Xi’an ChinaDepartment of Inflammation Biology School of Immunology and Microbial Sciences King’s College London, Guy’s Hospital London United KingdomDepartment of Inflammation Biology School of Immunology and Microbial Sciences King’s College London, Guy’s Hospital London United KingdomDepartment of Inflammation Biology School of Immunology and Microbial Sciences King’s College London, Guy’s Hospital London United KingdomDepartment of Inflammation Biology School of Immunology and Microbial Sciences King’s College London, Guy’s Hospital London United KingdomCore Research Laboratory the Second Affiliated Hospital, School of Medicine Jiaotong University Xi’an ChinaCore Research Laboratory the Second Affiliated Hospital, School of Medicine Jiaotong University Xi’an ChinaThrombosis Research Institute London United KingdomDepartment of Imaging Imperial College Healthcare NHS Trust Charing Cross Hospital London United KingdomDepartment of Cardiology Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou ChinaCardiovascular Division King’s College London James Black Centre London United KingdomSchool of Bioscience & Medicine Faculty of Health and Medical Sciences University of Surrey Guildford United KingdomDepartment of Inflammation Biology School of Immunology and Microbial Sciences King’s College London, Guy’s Hospital London United KingdomDepartment of Inflammation Biology School of Immunology and Microbial Sciences King’s College London, Guy’s Hospital London United KingdomBackground Anticoagulants induce atherosclerosis regression in animal models but exploiting this clinically is limited by bleeding events. Here we test a novel thrombin inhibitor, PTL060, comprising hirulog covalently linked to a synthetic myristoyl electrostatic switch to tether to cell membranes. Methods and Results ApoE−/− mice were fed chow or high‐fat diets, before transplantation of congenic aortic segments or injection of PTL060, parental hirulog, control saline, or labeled CD11b positive cells. Aortic transplants from transgenic mice expressing anticoagulants on endothelium did not develop atherosclerosis. A single intravenous injection of PTL060, but not hirulog inhibited atheroma development by >50% compared with controls when assessed 4 weeks later. Mice had prolonged bleeding times for only one seventh of the time that PTL060 was biologically active. Repeated weekly injections of PTL060 but not hirulog caused regression of atheroma. We dissected 2 contributory mechanisms. First, the majority of CCR2+ (C‐C chemokine receptor type 2+) monocytes recruited into plaques expressed CCR7 (C‐C chemokine receptor type 7), ABCA1 (ATP‐binding cassette transporter – 1), and interleukin‐10 in PTL060 mice, a phenotype seen in <20% of CCR2+ recruits in controls. Second, after several doses, there was a significant reduction in monocyte recruits, the majority of which were CCR2‐negative with a similar regression‐associated phenotype. Regression equivalent to that induced by intravenous PTL060 was induced by adoptive transfer of CD11b+ cells pre‐coated with PTL060. Conclusions Covalent linkage of a myristoyl electrostatic switch onto hirulog in PTL060 uncouples the pharmacodynamic effects on hemostasis and atherosclerosis, such that plaque regression, mediated predominantly via effects on monocytes, is accompanied by only transient anticoagulation.https://www.ahajournals.org/doi/10.1161/JAHA.119.014811atherosclerosisregressionthrombinthrombin inhibitor |
| spellingShingle | Daxin Chen Ke Li Sam Festenstein Julieta Karegli Hannah Wilkinson Hugh Leonard Lin‐Lin Wei Ning Ma Min Xia Henry Tam Jian‐an Wang Qingbo Xu John H. McVey Richard A. G. Smith Anthony Dorling Regression of Atherosclerosis in ApoE−/− Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel “Cytotopic” Anti‐Thrombin Without Prolonged Anticoagulation Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atherosclerosis regression thrombin thrombin inhibitor |
| title | Regression of Atherosclerosis in ApoE−/− Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel “Cytotopic” Anti‐Thrombin Without Prolonged Anticoagulation |
| title_full | Regression of Atherosclerosis in ApoE−/− Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel “Cytotopic” Anti‐Thrombin Without Prolonged Anticoagulation |
| title_fullStr | Regression of Atherosclerosis in ApoE−/− Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel “Cytotopic” Anti‐Thrombin Without Prolonged Anticoagulation |
| title_full_unstemmed | Regression of Atherosclerosis in ApoE−/− Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel “Cytotopic” Anti‐Thrombin Without Prolonged Anticoagulation |
| title_short | Regression of Atherosclerosis in ApoE−/− Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel “Cytotopic” Anti‐Thrombin Without Prolonged Anticoagulation |
| title_sort | regression of atherosclerosis in apoe mice via modulation of monocyte recruitment and phenotype induced by weekly dosing of a novel cytotopic anti thrombin without prolonged anticoagulation |
| topic | atherosclerosis regression thrombin thrombin inhibitor |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.119.014811 |
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