# IL-1 Beta Signaling Promotes Atherosclerotic Calcification and Cardiovascular Risk

> **NIH NIH P20** · OCEAN STATE RESEARCH INSTITUTE, INC. · 2021 · $310,143

## Abstract

Coronary artery disease from calcific atherosclerosis is the leading cause of morbidity and mortality in the 
world. The calcium composition of atherosclerotic plaque has predictive value in terms of cardiovascular 
events. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that 
promote this process are minimally understood. Recently, the inflammatory cytokine, IL-1β, was identified to be 
increased in calcifying atherosclerotic aortas from ApoE-/- background mice fed a high fat diet. Moreover, 
plaque and serum from mice with progressive calcification demonstrated increased expression of IL-1β. 
Treatment with the IL-1 receptor antagonist inhibited atherosclerotic calcification. IL-1β expression was a key 
driver of vascular smooth muscle cell calcium deposition by its ability to promote expression of the osteogenic 
transcription factors, RUNX2, SOX9, OSX and MSX2. Bone marrow transplantation confirmed that progressive 
calcification of plaque is attributable to the hematopoietic compartment. Several key questions remain: 1) are 
macrophages the key cellular source of plaque IL-1β during atherosclerotic calcification; 2) do vascular smooth 
muscle cells take on an inflammatory phenotype to promote plaque IL-1β expression; 3) what are the effects of 
IL-1 receptor signaling on both plaque macrophages and vascular smooth muscle cells; 4) how does IL-1 
receptor signaling lead to an osteogenic gene program; and 5) can IL-1β serve as a biomarker of progressive 
calcification in patients with coronary artery disease. Preliminary data demonstrated that macrophages appear 
associated with expression of IL-1β in plaque, and consequently, IL-1β signaling through its receptor may play 
an autocrine positive feedback role in promoting further IL-1β expression by macrophages. Vascular smooth 
muscle cells, in contrast, appear to play a responsive role to IL-1β signaling by activating an osteogenic gene 
program. However, global deletion of the IL-1 receptor demonstrated conflicting data about whether 
nonspecific inhibition of IL-1β signaling can protect against plaque vulnerability, indicating further study to 
delineate cell-specific contributions in this pathway is required. The hypothesis is that macrophage expression 
of IL-1β in atherosclerotic plaque and consequent vascular cell IL-1 receptor signaling lead to inflammatory 
atherosclerotic calcification resulting in increased risk of plaque rupture. Aim 1 will define macrophage IL-1β 
expression as the critical to inflammatory atherosclerotic calcification. Aim 2 will determine the respective roles 
of macrophage and smooth muscle cell IL-1 receptor signaling in inflammatory atherosclerotic calcification and 
osteogenic transcription factor expression. Aim 3 will validate serum IL-1β as a critical biomarker of 
progressive coronary artery calcification in patients. Confirming that a macrophage IL-1β signaling axis is a 
central mechanism in inflammatory...

## Key facts

- **NIH application ID:** 10200079
- **Project number:** 5P20GM103652-09
- **Recipient organization:** OCEAN STATE RESEARCH INSTITUTE, INC.
- **Principal Investigator:** Alan Ross Morrison
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $310,143
- **Award type:** 5
- **Project period:** 2013-09-20 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200079

## Citation

> US National Institutes of Health, RePORTER application 10200079, IL-1 Beta Signaling Promotes Atherosclerotic Calcification and Cardiovascular Risk (5P20GM103652-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10200079. Licensed CC0.

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