# Role of CITED2 in cardiovascular disease

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $402,500

## Abstract

Project Summary / Abstract
Heart disease accounts for 1 in 7 of all deaths in the USA, the majority of which are caused by atherosclerotic
plaques. Atherosclerosis and its complications are the leading cause of disability and deaths worldwide. In addition,
they also significantly contribute to the health care financial burden. Therefore, there is a clear need for the
development of novel therapies aimed at new signaling pathways and gene targets. Treatment strategies targeting
broad inflammatory and metabolic gene programs are desirable to achieve complete cessation and reversal of
plaque development. There is an increasing appreciation that transcriptionally dynamic macrophages are a key
player in the pathogenesis of atherosclerosis. We have established that CITED2 represents a molecular “switch,” that
promotes anti-atherogenic macrophage activation while repressing harmful pro-atherogenic phenotypes. Our
preliminary studies revealed that, (a) CITED2 expression is attenuated in human and murine atherosclerotic plaque
macrophages; (b) Anti-atherogenic stimuli enhance and pro-atherogenic agents attenuate CITED2 expression in
human, and murine macrophages; (c) Deficiency of Cited2 enhance macrophage lipid accumulation and foam cell
formation; (d) Reduction in Cited2 expression results in heightened basal levels of lipid influx gene while significantly
diminished lipid metabolism and efflux gene expression; (e) Myeloid-specific deficiency of Cited2 significantly
elevated high-fat diet induced atherosclerotic lesion formation in vivo. (f) Cited2 executes atheroprotective functions
by cooperating with PPARγ while antagonizing IRF1 activation in macrophages. Based on these observations, we
hypothesize that CITED2 is a critical negative regulator of macrophage pro-inflammatory activation, foam cell
formation and atherogenesis. We propose following aims to determine the precise role macrophage CITED2 in the
pathogenesis of atherosclerosis. In Aim 1: To dissect the precise molecular mechanism by which CITED2 regulates
macrophage inflammatory and lipid homeostasis gene expression. In Aim 2: To investigate the role of CITED2 in
macrophage lipid homeostasis and foam cell formation. In Aim 3: To examine the impact of myeloid-CITED2
deficiency on the pathogenesis of atherosclerosis. At the conclusion of these studies, we will have expanded our
fundamental insights into the molecular role of CITED2 in atherogenesis. Thus, the outcome of our studies may
provide novel opportunities to design therapeutic intervention in the treatment of human lipid metabolic disorders.

## Key facts

- **NIH application ID:** 10110026
- **Project number:** 5R01HL141423-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Ganapati Holanagadde Mahabaleshwar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2018-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110026

## Citation

> US National Institutes of Health, RePORTER application 10110026, Role of CITED2 in cardiovascular disease (5R01HL141423-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10110026. Licensed CC0.

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