Interleukin-1 beta promotes atheroprotective changes in late stage atherosclerotic lesions

Project: Research


  • Richard Baylis (PI)


Rupture of atherosclerotic plaques leading to myocardial infarction or stroke is the largest cause of death worldwide. Despite decades of research, the mechanisms leading to plaque rupture remain poorly understood. It is generally accepted that lesions with a high smooth muscle cell (SMC) to macrophage ratio are less likely to rupture. However, in atherosclerosis, SMC down-regulate their characteristic markers and express markers of other cells types. Indeed, rigorous SMC lineage tracing studies by our lab have shown that >80% of SMC within lesions were undetectable using traditional markers meaning the number of SMC within lesions been grossly underestimated. In addition - contrary to dogma - we have shown that SMC are not always beneficial but can be either atheroprotective or -promoting depending on their phenotypic transitions. Taken together, these studies highlight the importance of identifying factors that promote beneficial changes in SMC phenotype.An ongoing clinical trial is testing neutralization of interleukin-1 beta in high-risk cardiovascular patients. The central hypothesis is that inflammation drives atherosclerosis, and that inhibition of inflammation will improve patient survival. However, there is a lack of preclinical evidence that neutralization of IL1 will confer beneficial effects in late-stage atherosclerosis. Indeed, recent studies from our lab, which included the applicant, showed that treatment of our SMC-lineage tracing mice with the Novartis anti-IL1 Ab after the formation of advanced atherosclerosis resulted in multiple changes consistent with reduced plaque stability including marked reductions in the number of SMC-derived cells within the fibrous cap, which were largely replaced by macrophage. Studies in this proposal will test the hypothesis that IL1 signaling in SMC is critical for maintenance of plaque stability in late-stage atherosclerosis. Aim 1 will test the hypothesis that the detrimental effects of anti-IL1 Ab treatment on late-stage atherosclerosis are primarily mediated through IL1 signaling in SMC. Aim 2 will test the hypothesis that higher levels of IL4 following anti-IL1 Ab treatment contributes to the deleterious shift in fibrous cap cellular composition. These studies will greatly increase our understanding of IL1 signaling in late-stage atherosclerosis and may identify approaches to augment current therapies to promote atheroprotective changes in SMC phenotypes and ultimately improve patient care.
Award amount$53,688.00
Award date07/01/2017
Program typeClinical Health Profession Student Training Progra
Award ID17CPRE33660372
Effective start/end date07/01/201709/29/2017