| First Author | Burzynski LC | Year | 2023 |
| Journal | Cardiovasc Res | Volume | 119 |
| Issue | 12 | Pages | 2179-2189 |
| PubMed ID | 37309666 | Mgi Jnum | J:357929 |
| Mgi Id | MGI:7542872 | Doi | 10.1093/cvr/cvad091 |
| Citation | Burzynski LC, et al. (2023) Thrombin-activated interleukin-1alpha drives atherogenesis, but also promotes vascular smooth muscle cell proliferation and collagen production. Cardiovasc Res 119(12):2179-2189 |
| abstractText | 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-1alpha (IL-1alpha) by thrombin, and generated a novel knock-in mouse in which thrombin cannot activate endogenous IL-1alpha [IL-1alpha thrombin mutant (IL-1alphaTM)]. METHODS AND RESULTS: Here, we show significantly reduced atherosclerotic plaque formation in IL-1alphaTM/Apoe-/- mice compared with Apoe-/- and reduced T-cell infiltration. However, IL-1alphaTM/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-1alphaTM/Apoe-/- mice, suggesting that thrombin inhibitors can affect atherosclerosis via reduced IL-1alpha activation. Finally, bone marrow chimeras show that thrombin-activated IL-1alpha 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-1alpha. This not only highlights the importance of interplay between systems during disease and the potential for therapeutically targeting IL-1alpha and/or thrombin, but also forewarns that IL-1 may have a role in plaque stabilization. |
