# Anti-Atherogenic Mechanisms of Drebrin

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $523,250

## Abstract

We discovered that the actin-binding protein, Drebrin, is abundantly expressed in smooth muscle cells (SMCs)
and is up-regulated in response to arterial injury in mice and to atherosclerosis in humans. Comparing WT
with Dbn-/+ mice, we found that Drebrin inhibits SMC migration and proliferation, both in vitro and in vivo,
through stabilization of actin filaments. In studies with SMC-specific Dbn-/- (SMC-Dbn-/-) mice, we found that
SMC Drebrin limits angiotensin II-induced remodeling of the ascending aorta, in a manner that correlates with
down-regulation of NADPH oxidase 1 (NOX1), decreased SMC reactive oxygen species (ROS) production and
reduced vascular inflammation. Thus, Drebrin constrains not only the migratory/proliferative SMC phenotype
but also the pro-inflammatory SMC phenotype evoked by vascular injury and angiotensin II. Congruently, we
found that atherosclerosis is greater in SMC-Dbn-/-/Ldlr-/- than in congenic SMC-Dbn+/+/Ldlr-/- mice. Because
SMC Drebrin negatively regulates atherosclerosis, our goals are to determine the mechanisms by which
Drebrin regulates SMC pro-inflammatory signaling and whether enhanced SMC expression of Drebrin can
inhibit atherogenesis. To this end, we performed SILAC/mass spectrometry studies on Dbn-/- and congenic
WT SMCs. We found that whereas in Dbn-/- SMCs the ROS-defensive enzyme Glutathione-S-transferase µ1
(GSTM1) is down-regulated, the pro-inflammatory cytokine CX3CL1 (fractalkine) is up-regulated: thus we will
investigate the role of these proteins in mediating the phenotype of Dbn-/- SMCs. Because endocytosis of
NOX1 regulates ROS generation and activation of pro-inflammatory NFκB signaling and Drebrin has been
shown to inhibit endocytosis, we will investigate whether Drebrin inhibits NOX1-mediated ROS generation by
inhibiting endocytosis. A major focus of our studies will be pro-atherogenic SMC-derived foam cells, which
SMC lineage tracing studies have shown, comprise ~40% of foam cells in atherosclerotic lesions. Our
Preliminary Studies show that, compared with cognate Dbnflox/flox SMCs, Dbn-/- SMCs induced to
transdifferentiate with cholesterol loading exhibited increased expression of the macrophage marker, CD68,
and Kruppel-like factor 4 (KLF4), a transcription factor required for SMC-to-foam cell transdifferentiation. By
grafting common carotid arteries from Dbnflox/flox and SMC-Dbn-/- mice into carotid arteries of congenic Apoe-/-
mice, we also show that Drebrin deficiency augments transdifferentiation of SMCs to CD68+ cells in vivo. We
will test the hypothesis that Drebrin inhibits atherogenesis by limiting SMC transdifferentiation into foam cells.
To do so, we will establish whether Drebrin inhibits SMC-to-foam cell transdifferentiation and associated pro-
inflammatory signaling, both in vitro and in vivo; determine if Drebrin inhibits SMC transdifferentiation through
ROS-dependent mechanisms; and define the roles of GSTM1 and CX3CL1 in mediating Drebrin’s inhibitory
effects on SMC transd...

## Key facts

- **NIH application ID:** 10071201
- **Project number:** 5R01HL147157-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** NEIL J. FREEDMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $523,250
- **Award type:** 5
- **Project period:** 2019-12-16 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071201

## Citation

> US National Institutes of Health, RePORTER application 10071201, Anti-Atherogenic Mechanisms of Drebrin (5R01HL147157-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10071201. Licensed CC0.

---

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