# Development of Rac-Targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis

> **NIH NIH R01** · OCEAN STATE RESEARCH INSTITUTE, INC. · 2020 · $54,357

## Abstract

PROJECT SUMMARY/ABSTRACT:
Coronary artery disease (CAD) from calcific atherosclerosis is the single leading cause of morbidity and
mortality worldwide. 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 small GTPase, Rac2, was
identified as a major inflammatory regulator of signaling that directs plaque osteogenesis. Atherosclerotic
aortas from ApoE-/- mice fed a high fat diet supplemented with cholesterol demonstrated dynamic expression
of Rac2 mRNA expression over time. Moreover, decreased Rac2 expression correlated with increased
atherosclerotic calcification, both in the experimental animal model and in human coronary artery
plaques. Rac2 -/-ApoE -/- mice helped to define a protective role of Rac2, which prevented progressive
calcification through its suppression of Rac1-dependent macrophage IL-1β expression. Plaque and serum
from mice with calcified plaque demonstrated increased expression of IL-1β, and moreover, treatment with the
IL-1 receptor antagonist inhibited the enhanced atherosclerotic calcification. IL-1β expression was a key driver
of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs,
including expression of the osteogenic transcription factors, RUNX2, SOX9, OSX and MSX2. Bone marrow
transplantation confirmed the progressive calcification of plaque attributable to Rac2 gene deletion was
dependent on the hematopoietic compartment. Several key questions remain: 1) what is the role of
macrophage Rac1 in plaque development and atherosclerotic calcification in standard experimental models; 2)
are macrophages the key cellular source of plaque IL-1β; 3) how does Rac2 suppress Rac1-dependent
macrophage IL-1β expression; and 4) are these signaling mechanisms relevant to calcified atherosclerotic
plaque from patients with coronary artery disease? The overall objective of the proposed studies is to
thoroughly answer these questions. Preliminary data demonstrate that Rac1 can be a key promoter of
macrophage IL-1β expression and that Rac2 and Rac1 may antagonize each other through competition for a
similar guanine nucleotide exchange factor, Tiam1, which is upregulated under conditions that activate IL-1β
expression. The hypothesis is that macrophage Rac signaling determines atherosclerotic plaque IL-1β
expression and consequent inflammatory atherosclerotic calcification, and thus disrupting this pathway can be
an effective strategy for the prevention and treatment of CAD. Aim1 will define the role of macrophage Rac1 in
plaque IL-1β expression and atherosclerotic calcification. Aim2 will confirm that Rac1 and Rac2 compete for
Tiam1, a critical Rac-GEf that is upregulated during macrophage inflammatory activation as well as during
experimental atherosclerosis, and that IL-...

## Key facts

- **NIH application ID:** 9999222
- **Project number:** 3R01HL139795-03S1
- **Recipient organization:** OCEAN STATE RESEARCH INSTITUTE, INC.
- **Principal Investigator:** Alan Ross Morrison
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $54,357
- **Award type:** 3
- **Project period:** 2018-01-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999222

## Citation

> US National Institutes of Health, RePORTER application 9999222, Development of Rac-Targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis (3R01HL139795-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999222. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*