Molecular Determinants of Arterial Remodeling in Atherogenesis

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 DESCRIPTION (provided by applicant): An unexpected connection between interleukin-1 (IL-1) biology and arterial remodeling has emerged from recent work. ApoE-/- mice deficient in the IL-1 signaling receptor (hence unresponsive to both IL-1 α and β isoforms) have impaired expansive remodeling during atherogenesis, attributable to reduced expression of matrix metalloproteinase (MMP)-3 by smooth muscle cells (SMCs), and exhibit evidence for plaque "instability", likely due to impaired SMC migration. Other very recent data have questioned the validity of results obtained with IL-1β deficient mice and have suggested a predominant contribution of the IL-1α isoform to atherogenesis. In view of the ability to target IL-1 isoforms selectively, as illustrated by our large ongoing study of neutralization of IL-1β in humans with atherosclerosis (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study, CANTOS, NCT01900600), rigorously defining the distinct regulation and contributions of the IL-1 isoforms to mechanisms related to arterial remodeling and atherogenesis assumes critical biological and clinical significance. Specific Aim 1 will test in vitro the novel hypothesis that moderate hypoxia an atherosclerosis-related stimulus that prevails in plaques, regulates IL-1α and IL-1β production in macrophages (MFs), by distinct biochemical and cell-biological mechanisms. Further, this Aim will test in human cells the ability of IL-1 isoforms to regulate proteases implicated in arterial remodeling in the prior funding periods. We will test the specific hypothesi that IL-1 isoforms each enable these cells to migrate and hence participate redundantly in fibrous-cap formation, and in expansive remodeling during atherogenesis. Specific Aim 2 will test in vivo the hypothesis that selective antibody neutralization of IL-1α or IL-1β in atherosclerosis-susceptible mice will limit mechanisms related to atherogenesis and evolution of established atheromata, and will not impair expansive remodeling or confer characteristics of "instability" on plaques, as does blockade of both isoforms. This approach will obviate the serious concerns recently raised regarding the use of Il1b-/- mice. Specific Aim 3 will test in humans the hypothesis that administration of an IL-1β-neutralizing antibody will dose-dependently lower (but not extinguish) blood levels of MMP-3 (and as resources permit) other proteinases implicated in plaque instability and arterial remodeling. This Aim will further test th hypothesis that individuals who develop thrombotic complications of atherosclerosis have higher plasma levels of these enzymes than matched individuals without such events in a nested case-control study within the placebo group of a large ongoing investigator-initiated clinical trial, CANTOS, a population selected for residual inflammatory burden.