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. Issue 13 (7th July 2020)

• Record Type: Journal Article
• Authors: Chen, Daxin; Li, Ke; Festenstein, Sam; Karegli, Julieta; Wilkinson, Hannah; Leonard, Hugh; Wei, Lin‐Lin; Ma, Ning; Xia, Min; Tam, Henry; Wang, Jian‐an; Xu, Qingbo; McVey, John H.; Smith, Richard A. G.; Dorling, Anthony
• Is Part Of: Journal of the American Heart Association. Volume 9:Issue 13(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-07-07
• Subjects: atherosclerosis -- regression -- thrombin -- thrombin inhibitor; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.119.014811
• Languages: English
• ISSNs: 2047-9980

Abstract

Abstract : 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.