# Macrophage Rac1 Signaling is required for the progression of Calcific Aortic Valve Disease and consequent Aortic Valve Stenosis

> **NIH NIH F31** · BROWN UNIVERSITY · 2020 · $11,254

## Abstract

ABSTRACT:
 Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis, affecting 25% of
people over the age of 65 years. Patients who progress to symptomatic, severe aortic valve stenosis have a
50% mortality within 2 years if left untreated by surgical or transcatheter aortic valve replacement (TAVR).
Currently, there is no medical therapy for the prevention or treatment of this CAVD. Moreover, surgery can be
a high-risk procedure for many older patients with multiple comorbidities. Inflammatory signaling appears to
play a key role in progression of calcification and may hold the potential to develop the first therapeutic
treatment of CAVD. However, the underlying mechanisms of inflammatory calcification are minimally
understood. Our laboratory has begun defining a novel inflammatory signaling pathway critical to progressive
vascular calcification in models of hypercholesterolemia. We determined macrophage Rac1-dependent
expression of the inflammatory cytokine, interleukin-1β (IL-1β), is required for progressive atherosclerotic
calcification. The role of macrophage Rac1-mediated IL-1β expression has never been evaluated in models of
calcific aortic valve disease. Unpublished preliminary data presented in this proposal demonstrates that this
Rac1-induced IL-1β expression can be upregulated in macrophages under conditions consistent with
hypercholesterolemia-induced CAVD. Using a hyperlipidemia-based mouse model (ApoE-/-) for CAVD and an
inducible macrophage Rac1-deletion (CSF1RmcmRac1fl/fl), we observed in a preliminary study that the
development of CAVD was dependent on macrophage-specific Rac1 signaling. Echocardiographic measures
for aortic valve stenosis, including elevated blood flow velocity and valve area, were decreased in mice after
inducible gene-deletion of macrophage Rac1. Histological assessment of the valve demonstrated reduced
valve thickness, decreased valve calcification and decreased fibrosis in the macrophage Rac1-deleted
animals. Moreover, we observed reduced circulating (serum) IL-1β levels in the macrophage Rac1-deleted
animals. Our group's previous work has indicated that IL-1β promotes bone-forming osteogenic transcription
factor expression and is strongly associated with vascular calcification in a macrophage Rac-dependent
manner. Considering observations of macrophage Rac1 on CAVD development, it's association with IL-1β,
and past findings on the contribution of IL-1β to calcification in vitro, we hypothesize that a macrophage-
specific Rac1-IL-1β signaling pathway is a critical inflammatory mechanism that drives the progression of
CAVD to severe aortic valve stenosis. Our specific aims are to determine the individual roles of both Rac1
activity and IL-1β in the promotion of CAVD and consequent aortic valve stenosis in vivo. Defining
mechanisms of CAVD is critical to the development of novel therapeutic interventions aimed at disrupting the
natural course of the disease.

## Key facts

- **NIH application ID:** 9933822
- **Project number:** 5F31HL147466-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Joshua Berus
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $11,254
- **Award type:** 5
- **Project period:** 2019-06-01 → 2020-09-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933822

## Citation

> US National Institutes of Health, RePORTER application 9933822, Macrophage Rac1 Signaling is required for the progression of Calcific Aortic Valve Disease and consequent Aortic Valve Stenosis (5F31HL147466-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933822. Licensed CC0.

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