Atherosclerosis is a chronic inflammatory disease and is the leading cause of morbidity and death in developed countries. However, there are still fundamental gaps in our knowledge of the underlying mechanisms that contribute to its development, and end-stage clinical events including plaque rupture with possible myocardial infarction or stroke. Although the dogma in the field is that an increased ratio of smooth muscle cells (SMC) to macrophages within lesions promotes plaque stability, there are major limitations in the experimental evidence for this model including major ambiguities regarding which cells within lesions are of SMC versus monocyte-macrophage origin and the mechanisms that control SMC and macrophage number and phenotype. Of major significance, studies employing unique SMC lineage tracing ApoE-/- mice developed by the Owens lab provide evidence that ~25% of cells within advanced lesions that are Mac2+ but negative for SMC markers including SM ?-actin (SM?A), are SMC- rather than macrophage-derived. Conversely, a significant fraction of SM?A+ fibrous cap cells, presumed to be SMC-derived, are not. Moreover, we have evidence in that a significant fraction of macrophage- derived cells show reduced macrophage marker expression but are SM?A+. Collectively, results show that macrophages may convert to SMC-like cells and SMC to macrophage-like cells. Moreover, results indicate that it is likely that many lesion cells have been mis-identified in previous studies in the field, thus greatly confounding our understanding of the mechanisms and factors that regulate phenotypic transitions of these cells. The central focus of this grant is to determine the effects of genetic or pharmacological inhibition of IL1? and IL1R1 signaling on phenotypic transitions of SMC and macrophages, as well as on the overall size and stability of late stage atherosclerotic lesions. Whereas there is good evidence that disruption of IL1? signaling inhibits formation of fatty streaks and early stage lesions, the role of IL1 in late stage lesions is unclear.
Aim 1 a will use novel utilize SMC and myeloid specific lineage tracing IL1R1 knockout mouse lines generated by our lab to test the hypothesis that IL1R1-dependent transitions in phenotype of SMC and macrophages within advanced atherosclerotic lesions play a critical role in determining overall plaque and lumen size, as well as lesion composition including multiple indices of plaque stability.
Aim 1 b will be o determine if phenotypic transitions observed in our mouse studies occur in human atherosclerotic lesions based on analysis of autopsy specimens using a highly novel epigenetic SMC lineage tracing method recently developed by our laboratory (Gomez et al., Nature Methods).
Aim 2 will determine if treatment of ApoE null mice with a Novartis mouse anti-IL1? antibody induces changes in lesion size, cellular composition, or indices of plaque stability, as well as transitions in SMC and/or macrophage phenotype.
The studies in this proposal are focused on testing the role of the cytokine IL1 in regulating transitions in the phenotype of smooth muscle cells and macrophages within advanced atherosclerotic plaques. These transitions are believed to be critical in determining the mechanical properties of plaques and possible clinical complications of atherosclerosis including plaque rupture with possible myocardial infarction (MI) or stroke which are responsible for >40% of all deaths in this country. Studies include testing a mouse variant of the Novartis Canakinumab IL1 neutralizing antibody currently being tested in the >17,000 patient CANTOS clinical trial, and as such will be highly relevant to interpreting the outcome of ongoing clinical trials, and identifying alternative therapeutic interventions should CANTOS results be negative, or therapies that might best complement IL1 inhibition should CANTOS results be positive.
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