# Targeted approach to the mitigation of abdominal aortic aneurysm

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $724,978

## Abstract

Project Summary
Abdominal aortic aneurysm (AAA) is characterized by progressive aortic dilation and rupture that leads to sudden
death. To date, there are no medicinal therapies to stop AAA from progressing to rupture, largely due to poor
understanding of not only effective molecular targets but also targeted delivery approaches. While studies have
traditionally focused on immune cells and endothelial cells, smooth muscle cells (SMCs) can undergo
inflammation and degeneration, and exacerbate AAA via secretion of proinflammatory cytokines and proteolytic
enzymes. Thus, controlling SMC inflammation and degeneration has the potential to mitigate AAA. Previously
our lab identified bromodomain protein-4 (BRD4) as a driver of SMC inflammation. BRD4 is a transcription co-
activator that recognizes histone acetylation sites where it facilitates the clustering of transcription enhancers
into super-enhancers, thereby mediating gene activation. Our team has demonstrated that pan-inhibition of BRD
function ameliorates AAA in mice, however the mechanisms that underlie the specific role of BRD4 in controlling
AAA-associated SMC inflammation and degeneration remain largely unknown. Here we present promising
findings that reveal an important physiological function of BRD4 in modulating AAA progression. Using cultured
SMCs, we find that BRD4 protein is increased upon exposure to pro-inflammation factors; and human lesions of
AAA also show elevated BRD4 expression. Mice with SMC-specific knockout of BRD4 develop resistance to
elastase-induced AAA, suggesting a potential pro-aneurysm role of BRD4. Genome-wide analysis reveal BRD4
enrichment at the gene of CCAAT enhancer binding protein delta (CEBPD), a master transcription factor that
controls SMC inflammation and degeneration. In elastase-induced AAA models, knockdown of CEBPD reduces
AAA size; conversely, overexpression of CEBPD in the SMC-specific BRD4 knockout aorta exacerbates AAA in
mice. Overall, these findings support the premise that BRD4/CEBPD may participate in the epigenetic control of
genes involved in SMC degeneration and inflammation associated with AAA. By resolving the physiologic role,
and the cellular and molecular underpinnings of BRD4-CEBPD-AAA, we can advance the pathophysiology of
AAA, and potentially gain novel therapeutic approaches to treat AAA. Our team has developed a novel
biomimetic AAA-homing nanoplatform. We envision that targeted delivery of BRD4-inactivating agents can
provide a potential effective means to mitigate AAA.

## Key facts

- **NIH application ID:** 10855663
- **Project number:** 1R01HL172888-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** SHAOQIN - GONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $724,978
- **Award type:** 1
- **Project period:** 2024-06-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855663

## Citation

> US National Institutes of Health, RePORTER application 10855663, Targeted approach to the mitigation of abdominal aortic aneurysm (1R01HL172888-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10855663. Licensed CC0.

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