Affiliation:
1. Section of CardioRespiratory Medicine, The Heart and Lung Research Institute, The University of Cambridge , Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0BB , UK
Abstract
Abstract
Aims
Atherosclerosis is driven by multiple processes across multiple body systems. For example, the innate immune system drives both atherogenesis and plaque rupture via inflammation, while coronary artery-occluding thrombi formed by the coagulation system cause myocardial infarction and death. However, the interplay between these systems during atherogenesis is understudied. We recently showed that coagulation and immunity are fundamentally linked by the activation of interleukin-1α (IL-1α) by thrombin, and generated a novel knock-in mouse in which thrombin cannot activate endogenous IL-1α [IL-1α thrombin mutant (IL-1αTM)].
Methods and results
Here, we show significantly reduced atherosclerotic plaque formation in IL-1αTM/Apoe−/− mice compared with Apoe−/− and reduced T-cell infiltration. However, IL-1αTM/Apoe−/− plaques have reduced vascular smooth muscle cells, collagen, and fibrous caps, indicative of a more unstable phenotype. Interestingly, the reduced atherogenesis seen with thrombin inhibition was absent in IL-1αTM/Apoe−/− mice, suggesting that thrombin inhibitors can affect atherosclerosis via reduced IL-1α activation. Finally, bone marrow chimeras show that thrombin-activated IL-1α is derived from both vessel wall and myeloid cells.
Conclusions
Together, we reveal that the atherogenic effect of ongoing coagulation is, in part, mediated via thrombin cleavage of IL-1α. This not only highlights the importance of interplay between systems during disease and the potential for therapeutically targeting IL-1α and/or thrombin, but also forewarns that IL-1 may have a role in plaque stabilization.
Funder
British Heart Foundation Grants
BHF Cambridge Centre for Research Excellence
Cambridge NIHR Biomedical Research Centre
Publisher
Oxford University Press (OUP)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
2 articles.
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