Niacin-mediated migration of monocyte-derived cells in atherosclerosis

  • Ingersoll, Molly (PI)

Project Details

Description

DESCRIPTION (provided by applicant): Atherosclerosis, a chronic inflammation of arteries, is characterized by lipoprotein and monocyte infiltration beneath the endothelium that develops into plaques. During resolution of inflammation, monocyte-derived cells migrate out of inflammatory foci. However, this does not occur in atherosclerotic plaques and instead phagocytes die, contributing to formation of a necrotic core. The necrotic core is a lipid and cellular debris pool beneath a fibrous cap, which is prone to rupture, the major event associated with mortality. The mechanisms that mobilize monocyte-derived cells to leave plaques are not known, but are of great interest since promoting such egress may lead to diminished necrotic cores within more stable plaques, providing new means to treat atherosclerosis and prevent mortality. Ongoing work in the Randolph lab, using a unique labeling protocol to trace migration of monocyte subsets in mouse atherosclerotic plaques, demonstrated that intake of 1% niacin supplemented diet promoted monocyte-derived cell egress from plaques rescuing monocytes from dying in necrotic cores and led to decreased necrotic cores (30%). Remarkably, this niacin-mediated egress was limited to only one of two monocyte subsets. However, a necessary step in labeling the second monocyte subset induced a dramatic increase in circulating cholesterol. While it is possible that only one subset is niacin-responsive, alternatively, the induced dyslipidemic environment may inhibit monocyte-derived cell egress from plaques. I hypothesize that niacin mediates emigration of monocyte-derived cells from plaques by provoking specific egress pathways which become suppressed during atherosclerosis, especially in a severely dislipidemic environment such as that induced during monocyte subset labeling. Specifically, I aim to (1) identify the pathway niacin uses to induce the egress of monocyte-derived cells from atherosclerotic plaques, with gene knockout and chimeric mice, to test the role of the niacin receptor PUMA-G and/or the increased availability of NAD+, of which niacin is a precursor molecule. Increased NAD+ may increase CD38 mediated ADP-ribosylation, which leads to calcium signaling-dependent migration. I will (2) determine if niacin-mediated migration is restricted to one monocyte subset using adoptive transfer of cell populations to rescue dyslipidemia and induce a migration-permissive environment. PUBLIC HEALTH RELEVANCE: Mechanisms to mobilize monocyte-derived cells to leave atherosclerotic plaques are of great interest since promoting such egress may lead to diminished necrotic cores and reduced mortality. This proposal will investigate niacin mediated cell migration.
StatusFinished
Effective start/end date1/07/0930/06/10

Funding

  • National Heart, Lung, and Blood Institute: $55,790.00
  • National Heart, Lung, and Blood Institute: $53,354.00

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