Integral to the pathogenesis of atherosclerosis is the transformation of vascular smooth muscle cells (SMCs) from a """"""""contractile"""""""" to a """"""""proliferative/migratory"""""""" phenotype, and growing evidence supports the view that factors enhancing SMC proliferation and migration also enhance atherosclerosis. On a molecular level, this SMC transformation involves cytoskeletal signaling and calcium signaling pathways, which are significantly modulated by calcium influx through transient receptor potential (TRP) channels-a family of nonselective cation channels in SMCs that upregulate when SMCs transition from the contractile to the proliferative/migratory phenotype. Activation of TRP channels is influenced by the underlying cytoskeleton and scaffolding proteins. Unresolved important questions include what proteins link TRP channels to cytoskeletal signaling pathways and how these proteins influence SMC migration. We have previously shown that TRP channels require the scaffolding protein Homer 1 for proper function, and that Homer 1 associates with Drebrin, an actin-binding protein highly expressed in SMCs. In our Preliminary Studies, we found that Drebrin expression is upregulated both during neointimal hyperplasia triggered by arterial injury and in atherosclerotic lesions of Apoe-/- mice, suggesting a role for Drebrin in the regulation of vascular remodeling during atherosclerosis. Compared with wild-type (WT) SMCs, SMCs from Drebrin haploinsufficient (Dbn-/+) mice migrate faster and have increased basal and PDGF-evoked TRP channel activity. Congruently, we found that Dbn-/+ mice developed more neointimal hyperplasia than WT mice in response to carotid endothelial denudation. Gene products that affect neointimal hyperplasia triggered by arterial injury almost invariably affect atherosclerosis in a concordant manner. For this reason we will test the hypothesis that Drebrin activity inhibits atherosclerosis as it inhibits neointimal hyperplasia. Moreover, because of the importance of TRP channels in SMC migration and the importance of Drebrin/Homer scaffolds in regulating TRP channels, we will test the hypothesis that the Drebrin inhibits SMC transformation to the proliferative/migratory phenotype through regulation of TRP channel function. To do so, we will pursue the following Specific Aims: (1) To determine whether Drebrin limits SMC migration/proliferation through regulation of TRP channel activity. We hypothesize that Drebrin reduces SMC migration/proliferation through inhibition of TRP channel activity. (2) To determine whether Drebrin reduces SMC migration through its effects on calcium signaling or through a direct effect on cytoskeletal remodeling. We hypothesize that Drebrin reduces SMC migration through inhibition of calcium signaling. (3) To determine whether Drebrin expression reduces atherosclerosis. We hypothesize that Drebrin reduces atherosclerosis by inhibiting SMC migration/proliferation.
The proposed research is relevant to public health because it will advance our understanding of the role of the actin-binding protein Drebrin in the pathogenesis of 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, which provides a potential link between cytoskeletal signaling and TRP channel activation in vascular smooth muscle during the pathogenesis of 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.
|Zhang, Lisheng; Wu, Jiao-Hui; Huang, Tai-Qin et al. (2018) Drebrin regulates angiotensin II-induced aortic remodelling. Cardiovasc Res 114:1806-1815|
|Jean-Charles, Pierre-Yves; Wu, Jiao-Hui; Zhang, Lisheng et al. (2018) USP20 (Ubiquitin-Specific Protease 20) Inhibits TNF (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates Atherosclerosis. Arterioscler Thromb Vasc Biol 38:2295-2305|
|Zhang, Zhushan; Huang, Tai-Qin; Nepliouev, Igor et al. (2017) Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity. Cardiooncology 3:|
|Stiber, Jonathan A; Wu, Jiao-Hui; Zhang, Lisheng et al. (2016) The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia. Arterioscler Thromb Vasc Biol 36:984-93|