Vascular smooth muscle cell (SMC) migration is a critical event in neointimal formation in the development of atherosclerosis and restenosis, Lysophosphatidic acid (LPA), is emerging as an important lipid mediator of the cellular events contributing to atherosclerosis. During the last grant period, using an LPA receptor knockout mouse model, we identified LPA receptor 1 as the major cell membrane receptor mediating LPA-induced SMC migration and neointimal formation. We also discovered the matricellular protein Cyr61 as the key molecule mediating LPA signaling, leading to SMC migration and neointimal formation. These findings established a new concept that Cyr61 bridges the LPA and integrin signaling pathways, leading to focal adhesion kinase (FAK) activation/SMC migration and neointimal formation. In this grant period, we propose to extend our investigation to identify the molecular mechanism by which LPA-Cyr61 induces SMC migration and the LPA-Cyr61 pathway contribution to atherogenesis. Very recently lineage-tracing studies reveal that a large portion of macrophage marker-positive cells in mouse and human atherosclerotic lesions are vascular SMC-derived cells, suggesting SMC migration/proliferation and differentiation play important roles in atherogenesis. Understanding of SMC migration mechanism will significantly contribute to understanding atherogenesis. To date, little is known about the nature and spatial-temporal regulation of the migration which drives kinases in the polarized leading edge of SMCs. Interestingly, our recent study revealed several exciting novel findings: 1) the novel pseudopodium- enriched atypical kinase 1 (PEAK1) activation is localized in the polarized leading edge of SMCs upon LPA treatment; 2) Cyr61 induces PEAK1 activation and 3) knockdown of PEAK1 blocked SMC migration, suggesting PEAK1 functions as a downstream key mediator of Cyr61, regulating SMC migration. Furthermore, we discovered that PEAK1 interacts with FAK, a key regulator of cell migration. We also observed that phosphorylated PEAK1 levels are highly increased in ApoE-/- atherosclerotic lesions. The function of the novel kinase PEAK1 in vascular disease is unknown. Our data suggest that PEAK1 is the novel mediator for FAK activation and SMC migration. Based on these new observations, we hypothesize that the LPA receptor- Cyr61-integrin-PEAK1-FAK axis mediates SMC cytoskeleton reorganization/migration and lesion formation in atherosclerosis. These hypotheses will be tested in the following specific aims.
Aim 1 : Determine the novel role of PEAK1/FAK interaction on the activation of the Src/PEAK1/FAK/Paxillin/Rac pathway and SMC migration.
Aim 2 : Dissect the novel mechanism by which Cyr61 interacts integrin-adhesion complex signaling, leading to membrane protrusion and cell migration using unique Cyr61 mutant SMCs from novel Cyr61dm/dm knock-in mice.
Aim 3 : Establish the roles of LPA receptors and Cyr61 in the development of atherosclerosis using our innovative LPA receptor/ApoE knockout, Cyr61dm/dm/ApoE-/- and SMC lineage tracing mouse models. The proposed studies are expected to identify novel targets for prevention and treatment of atherogenesis

Public Health Relevance

The central goal of this proposal is to reveal the pathological role of lysophosphatidic acid (LPA), which is involved in the development of atherosclerosis, a type of hardening of the arteries. Cardiovascular disease is the number one cause of death and disability in the United States. Understanding the basic mechanisms of atherosclerosis paves the way for new prevention and treatment approaches.

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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Gao, Yunling
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University of Texas of the Permian Basin
Schools of Arts and Sciences
United States
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An, Dong; Hao, Feng; Hu, Chen et al. (2017) JNK1 Mediates Lipopolysaccharide-Induced CD14 and SR-AI Expression and Macrophage Foam Cell Formation. Front Physiol 8:1075
Dou, Quanlin; Hao, Feng; Sun, Longsheng et al. (2017) CRE and SRE mediate LPA-induced CCN1 transcription in mouse aortic smooth muscle cells. Can J Physiol Pharmacol 95:275-280
Hu, Chen; Xu, Junjie; Zeng, Linlin et al. (2017) Pen-2 and Presenilin are Sufficient to Catalyze Notch Processing. J Alzheimers Dis 56:1263-1269
Dong, Yunzhou; Wu, Yong; Cui, Mei-Zhen et al. (2017) Lysophosphatidic Acid Triggers Apoptosis in HeLa Cells through the Upregulation of Tumor Necrosis Factor Receptor Superfamily Member 21. Mediators Inflamm 2017:2754756
An, Dong; Hao, Feng; Zhang, Fuqiang et al. (2017) CD14 is a key mediator of both lysophosphatidic acid and lipopolysaccharide induction of foam cell formation. J Biol Chem 292:14391-14400
Huang, Yujian; Wang, Yongzhong; Tan, Li et al. (2016) Nanospherical arabinogalactan proteins are a key component of the high-strength adhesive secreted by English ivy. Proc Natl Acad Sci U S A 113:E3193-202
Hu, Chen; Zeng, Linlin; Li, Ting et al. (2016) Nicastrin is required for amyloid precursor protein (APP) but not Notch processing, while anterior pharynx-defective 1 is dispensable for processing of both APP and Notch. J Neurochem 136:1246-1258
Zeng, Linlin; Hu, Chen; Zhang, Fuqiang et al. (2015) Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced ?-Secretase-dependent and -independent Apoptosis, Respectively. J Biol Chem 290:18269-80
Cui, Mei-Zhen (2015) Potential therapeutics for myocardial ischemia-reperfusion injury. Focus on ""Induction of cardioprotection by small netrin-1-derived peptides"". Am J Physiol Cell Physiol 309:C97-9
Zhang, Fuqiang; Hao, Feng; An, Dong et al. (2015) The matricellular protein Cyr61 is a key mediator of platelet-derived growth factor-induced cell migration. J Biol Chem 290:8232-42

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