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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.

Research output: Contribution to journalArticle

Daxin Chen, Ke Li, Sam Festenstein, Julia Karegli, Hannah Wilkinson, Hugh Leonard, Lin-Lin Wei, Ning Ma, Min Xia, Tam Henry, Jian An Wang, Qingbo Xu, John H McVey, Richard Smith, Anthony Dorling

Original languageEnglish
JournalJournal of the American Heart Association
DOIs
Publication statusPublished - 2 Jul 2020

Documents

  • Chen et al_final version

    Chen_et_al_final_version.pdf, 27.6 MB, application/pdf

    22/05/2020

    Accepted author manuscript

    Unspecified

King's Authors

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 labelled CD11b positive cells. Aortic transplants from transgenic mice expressing anticoagulants on endothelium did not develop atherosclerosis. A single IV injection of PTL060, but not hirulog inhibited atheroma development by >50% compared to controls when assessed 4 weeks later. Mice had prolonged bleeding times for only 1/7th of the time that PTL060 was biologically active. Repeated weekly injections of PTL060 but not hirulog caused regression of atheroma. We dissected two contributory mechanisms. First, the majority of CCR2+ monocytes recruited into plaques expressed CCR7, ABCA1 and IL-10 in PTL060 mice, a phenotype seen in fewer than 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 IV 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 haemostasis and atherosclerosis, such that plaque regression, mediated by predominantly via effects on monocytes, is accompanied by only transient anticoagulation.

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