Interleukin-1 distinctly modulates smooth muscle cell phenotype and plays dual protective roles in advanced atherosclerosis

Alexander, Matthew Robert, Department of Molecular Physiology and Biological Physics, University of Virginia
Owens, Gary, Department of Molecular Physiology and Biological Physics, University of Virginia

Atherosclerosis is a chronic disease involving plaque development within large arteries. Clinical complications of atherosclerosis arise primarily through atherosclerotic plaque destabilization and narrowing of the vessel lumen. Previous studies have suggested an important role for inflammation in plaque destabilization. Smooth muscle cells (SMCs) contribute to atherosclerotic plaque development at least in part through modulation of their phenotype, however it is unclear whether SMCs can undergo phenotypic modulation to a distinct inflammatory state that may promote plaque destabilization. Studies within this dissertation have thus focused on determining whether the inflammatory cytokine interleukin-1 (IL-1) modulates SMC phenotype to a distinct inflammatory state, and whether IL-1 regulates atherosclerotic plaque stability and luminal narrowing. Studies utilized genome-wide gene expression analysis to demonstrate that compared to the classical mediator of SMC phenotypic modulation, plateletderived growth factor (PDGF), IL-1 distinctly induced expression of numerous pro-inflammatory genes in cultured SMCs. In addition, IL-1-induced upregulation of multiple inflammatory genes and repression of SMC differentiation marker genes was mediated by the transcription factor nuclear factor kappa B (NFκB). Finally, in mouse atherosclerotic lesions, cells were identified expressing the marker of an IL-1β-stimulated inflammatory SMC phenotype, chemokine (C-C motif) ligand 20, but not the PDGF-DD-induced gene, regulator of G-protein signaling 17, suggesting that a distinct inflammatory SMC phenotype may exist within atherosclerotic plaques in vivo. ii IL-1 has been shown to promote atherosclerotic plaque formation, however the role of IL-1 in regulating plaque stability and luminal narrowing is unclear. Surprisingly, atheroprone mice with genetic deficiency of the interleukinreceptor 1 type I (IL1R1) exhibited enhanced features of plaque instability and increased luminal narrowing relative to controls. Additionally, IL1R1-deficient mice exhibited reduced matrix metalloproteinase-3 (MMP3) levels within atherosclerotic vessels relative to controls, MMP3-deficient mice exhibited increased luminal narrowing, and MMP3 mediated IL-1-induced SMC migration through matrix, suggesting that reductions in MMP3 production may at least partially mediate the detrimental effects of Il1r1 deficiency. Taken together, results demonstrate that although IL-1 modulates SMC phenotype to a distinct inflammatory state in vitro, in advanced atherosclerosis IL-1 actually plays a dual atheroprotective role through enhancing features of atherosclerotic plaque stability and limiting luminal narrowing.

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PHD (Doctor of Philosophy)
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