Abstract 215: Rac-Signaling as a Critical Determinant of IL-1beta-Dependent Atherosclerotic Calcification
| Autor: | Abigail L Healy, Nicolle Ceneri, Chris Mantsounga, Alan R Morrison |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 37 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvb.37.suppl_1.215 |
| Popis: | Coronary artery disease caused by atherosclerosis is the leading cause of morbidity and mortality in the world. Calcification of atherosclerotic plaque has predictive value in terms of cardiovascular event risk and mortality. Plaque calcium composition appears critical to determining cardiovascular risk; microcalcification has been associated with more vulnerable plaque phenotypes, while somewhat paradoxically, densely calcified plaque is associated with more stable disease. Inflammation can influence calcification of plaque, but immune modulators of plaque calcification are minimally defined. Rac1 and Rac2 are small GTPases that influence cytokine expression in plaque macrophages. We have defined a Rac-based signaling mechanism that regulates macrophage IL-1β expression. Using an atherosclerotic-prone mouse model, we identified that progressive calcification depends on altered Rac expression and activation (GTP-binding) through consequent effects on macrophage IL-1β production and IL-1R signaling. IL-1β production and its downstream signaling were critical determinants of atherosclerotic plaque calcification. In short, Rac2 expression determined the degree of Rac1 GTP-binding, acting as a brake on Rac1-dependent IL-1β production, whereas macrophage IL-1β production and atherosclerotic calcification depended on myeloid Rac1. Therapeutic inhibition of macrophage Rac-mediated IL-1β expression has the potential to be a treatment strategy for progressive, inflammatory atherosclerotic calcification. |
| Databáze: | OpenAIRE |
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