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 1 (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 NF?B 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 transdifferentiation and pro-inflammatory signaling.

Public Health Relevance

The proposed research is relevant to public health because it will advance our understanding of the mechanisms by which the actin-binding protein, Drebrin, inhibits the development of atherosclerosis. Atherosclerosis and vascular inflammation are reduced in mice by the activity of Drebrin, a protein that is expressed in vascular smooth muscle cells and that increases its expression level in the context of human atherosclerosis. Atherosclerosis is a leading medical condition, which can lead to significant morbidity and mortality as the result of myocardial infarction, congestive heart failure, and stroke. Understanding the function of Drebrin in vascular smooth muscle and the mechanisms by which it inhibits atherosclerosis has the potential to lead to the identification of new therapeutic interventions to treat this important disorder. Thus, the proposed research is relevant to the NIH?s mission of developing fundamental knowledge that will help reduce the burdens of illness and disability.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Olive, Michelle
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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