Bone marrow-derived endothelial progenitor cells (EPCs) hold great promise in regenerative medicine for the treatment of chronic or currently incurable cardiovascular diseases. The homing of EPCs to neovascular areas requires a coordinated sequence of multistep events, including chemoattraction, adhesion, and invasion, before differentiation into mature endothelial cells and incorporation into active neovasculature. Impaired EPC function in mobilization and homing affects vascular homeostasis and also compensatory angiogenesis. Circulating EPCs may thus provide an endogenous repair mechanism to counteract ongoing risk factor-induced endothelial injury and to replace dysfunctional endothelium. Members of the SMYD protein family represent an emerging group of lysine methyltransferases that are particularly abundant in the cytoplasm, with SMYD1 being most highly expressed in heart and skeletal muscles. SMYD1 knockout in mice results in early embryonic lethality due to disruption of cardiac differentiation and morphogenesis. It has been reported that the chemokine receptor CXCR2 and its cognate ligands mediate EPC recruitment and angiogenesis in endothelial injury and myocardial ischemia. Compared with what is known about CXCR2 phosphorylation and other posttranslational modifications (such as ubiquitination and glycosylation), nothing is known about the lysine methylation of CXCR2, and how CXCR2 methylation might influence CXCR2 activation and signaling, especially as involved in EPC biology. The long-term goal is to better understand the molecular mechanisms regulating EPC homing and angiogenesis, in the hope of revealing novel therapeutic targets for certain vascular diseases. The hypothesis of this application is that lysine methylation of CXCR2 by the histone methyltransferase SMYD1 regulates EPC homing and angiogenesis through modulating CXCR2 activation and signaling.
The specific aims of this project are: first, to examine the effect of SMYD1 in modulating CXCR2- mediated EPC migratory and angiogenic activities; and second, to characterize the molecular mechanism by which SMYD1 regulates CXCR2-mediated EPC function. A combination of multiple approaches, i.e., molecular and biochemical techniques, cellular functional assays, and in vivo animal models, will be used to test the hypothesis. The proposed research is innovative because by exploring a previously unrecognized lysine methylation of CXCR2 in modulating EPC functions, new potential therapeutic paradigms may evolve for EPC- based cell therapy in aberrant angiogenesis. In addition, this is the first study to investigate methylation of CXCR2 that may be the first non-histone target/substrate of the histone lysine methyltransferase SMYD1. The anticipated results from this proposal are the identification of a yet-unexplored role of the lysine methyltransferase SMYD1 in regulating CXCR2 function and the establishment of a novel link between lysine methylation, chemokine receptor activation, and endothelial signaling during vascular development and injury. Such results are expected to have an important impact in EPC biology, because the mechanistic characterization of the SMYD1-catalyzed CXCR2 lysine methylation are likely to provide valuable information for enhancing EPC-based cell therapy for certain vascular diseases, as well as to fundamentally advance the field of chemokine receptor biology.

Public Health Relevance

Endothelial progenitor cells (EPCs) are released from the bone marrow during cardiovascular diseases including vascular ischemic injury, with their primary function being to repair injured blood vessels and restore normal cardiovascular function. The proposed study aims to explore a previously-unrecognized role and the underlying molecular mechanisms of lysine methylation of the chemokine receptor CXCR2 by a histone methyltransferase SMYD1 in modulating EPC migration and angiogenesis. The proposed research is relevant to public health because the mechanistic studies of CXCR2 methylation are likely to provide valuable information and potential therapeutic targets for enhancing EPC-based cell therapy for certain vascular diseases, as well as to fundamentally advance the field of chemokine receptor biology. Therefore, the work detailed in this proposal is relevant to NIH's mission as it pertains to the pursuit of fundamental knowledge regarding the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL128647-01
Application #
8945632
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2015-07-01
Project End
2020-04-30
Budget Start
2015-07-01
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Wayne State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Farooq, Shukkur M; Hou, Yuning; Li, Hainan et al. (2018) Disruption of GPR35 Exacerbates Dextran Sulfate Sodium-Induced Colitis in Mice. Dig Dis Sci 63:2910-2922
Jiang, Haiyue; Huang, Shuai; Gao, Feng et al. (2018) Diterpenoid alkaloids from Aconitum brevicalcaratum as autophagy inducers. Nat Prod Res :1-6
Chen, Lin; Huang, Shuai; Li, Chun Ying et al. (2018) Pyrrolizidine alkaloids from Liparis nervosa with antitumor activity by modulation of autophagy and apoptosis. Phytochemistry 153:147-155
Yu, Huimei; Jiang, Yuanyuan; Liu, Lanxin et al. (2017) Integrative genomic and transcriptomic analysis for pinpointing recurrent alterations of plant homeodomain genes and their clinical significance in breast cancer. Oncotarget 8:13099-13115
Spellmon, Nicholas; Sun, Xiaonan; Xue, Wen et al. (2017) New open conformation of SMYD3 implicates conformational selection and allostery. AIMS Biophys 4:1-18
Holcomb, Joshua; Spellmon, Nicholas; Zhang, Yingxue et al. (2017) Protein crystallization: Eluding the bottleneck of X-ray crystallography. AIMS Biophys 4:557-575
Spellmon, Nicholas; Holcomb, Joshua; Niu, Andrea et al. (2017) Structural basis of PDZ-mediated chemokine receptor CXCR2 scaffolding by guanine nucleotide exchange factor PDZ-RhoGEF. Biochem Biophys Res Commun 485:529-534
Zhao, B; Hu, W; Kumar, S et al. (2017) The Nogo-B receptor promotes Ras plasma membrane localization and activation. Oncogene 36:3406-3416
Doughan, Maysaa; Spellmon, Nicholas; Li, Chunying et al. (2016) SMYD proteins in immunity: dawning of a new era. AIMS Biophys 3:450-455
Hou, Yuning; Guan, Xiaoqing; Yang, Zhe et al. (2016) Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers. World J Gastrointest Oncol 8:282-8

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