Harrison College of Pharmacy

Current Funding

Non-platelet P2Y Receptor in Vascular Inflammation and Thrombogenesis
Funder: NIH, 1R01HL125279-01A1
Date: 2017-22
Role: Principal Investigator
Total Cost: $1,850,000

Laboratory Personnel

Graduate Students

• Yi Shi
• Shenqi Qian

External Links

• Pubmed Publications
• Google Scholar
• NCBI MyBibliography
• Curriculum Vitae [PDF]

Research Interests

Overview - A long term goal of my laboratory is to understand mechanisms by which G protein-coupled receptor (GPCR) signaling leads to vascular inflammation, atherosclerosis, thrombosis, and metabolic diseases. I have been fouced on two GPCRs – The purinergic or nucleotide P2Y2 receptor and the chemokine receptor CXCR7. Both research programs rely heavily on molecular biology, biochemical, and pharmacological methods in cultured vascular endothelial cells, blood monocytes/macrophages, and (pre)adipocytes. Genetic approaches like new mouse models with tissue-specific deletion of the P2Y2 receptor or CXCR7 genes are also employed for in vivo study. An overriding objective of the research programs is to identify novel molecular targets for anti-inflammation therapy with a focus on cardiometabolic diseases.

P2Y2 Receptor Signaling and Vascular Inflammation - The P2Y2 receptor, an ATP/UTP-sensitive nucleotide receptor has been my favorite target. My lab was the first to show that activation of non-platelet P2Y receptors, such as endothelial P2Y2 receptor, induces dramatic up-regulation of tissue factor, the initiator of coagulation cascade. We also found that the mechanism underlying P2Y2 receptor-controlled tissue factor expression is different from that of TNFα. After years of rigorous study, we identified a new P2Y2 receptor-responsive AP-1 site and discovered the first repressor Fra-1 for the tissue factor gene. I believe my accumulated achievement in this area will change the paradigm of current thoughts on the role of P2Y receptor in thrombosis and will define a new link between vascular inflammation and thrombosis. The lab is currently aiming for identification of new biased ligands for this receptor which could be a new treatment option for inflammatory cardiovascular and metabolic diseases.

CXCR7 Signaling in Cardiometabolic Disease - My second area focuses on the chemokine receptor CXCR7 (also termed ACKR3). We are the first to report CXCR7 signaling function during monocyte-to-macrophage differentiation and its significance in promoting vascular inflammation and atherosclerosis. This has been extended recently into adipocyte differention and functions. The lab is currently revealing new receptor signaling mechanism for CXCR7 in control of endothelial and adipocyte functions in the context of cardiovascular and metabolic diseases.

Selected Publications

Google Scholar i10-Index of 20

Google Scholar H-index of 17

• Peng Q, Qian S, Alqahtani S, Panizzi P, Shen J. The P2Y2 Nucleotide ReceptorMediates Monocyte Tissue Factor Expression and Endotoxemia Death in Mice. doi: https://doi.org/10.1101/2021.12.28.474395 (Accepted preprint in bioRxiv, 2022).
• Peng Q, Alqahtani S, Nasrullah MZA, Shen J. Functional evidence for biased inhibition of G protein signaling by YM-254890 in human coronary artery endothelial cells. Eur J Pharmacol. 2021;891:173706. doi: 10.1016/j.ejphar.2020.173706. PMCID: PMC7770062
• Shi Y, Riese DJ 2nd, Shen J. The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer. Front Pharmacol. 2020 Dec 8;11:574667. doi: 10.3389/fphar.2020.574667.
• Li H, Zhao Z, Ling J, Pan L, Zhao X, Zhu H, Yu J, Xie B, Shen J, Chen W. USP14 Promotes K63-linked RIG-I Deubiquitination and Suppresses Antivira Immune Responses. Eur J Immunol. 2019; 49(1):42-53. PMID: 30466171
• Wang C, Chen W, Shen J. CXCR7 Targeting and Its Major Disease Relevance. Front Pharmacol. 2018;9:641. doi: 10.3389/fphar.2018.00641. PMID: 29977203
• Zhao X, Pu D, Zhao Z, Zhu H, Li H, Shen Y, Zhang X, Zhang R, Shen J, Xiao W, Chen W. Teuvincenone F Suppresses LPS-Induced Inflammation and NLRP3 Inflammasome Activation by Attenuating NEMO Ubiquitination. Front Pharmacol. 2017;8:565. doi: 10.3389/fphar.2017.00565. PMID: 28878677
• Liu Y, Zhang L, Wang C, Roy S, Shen J. Purinergic Receptor P2Y2 Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells: New AP-1 Transcription Factor Site and Negative Regulator. J Biol Chem. 2016 291(4):1553-63. (selected as Paper of the Week, ranked top 2% and highlighted by JBC editors)
• Ma W, Liu Y, Wang C, Zhang L, Crocker L, Shen J. Atorvastatin Inhibits CXCR7 Induction to Reduce Macrophage Migration.  Biochem Pharmacol. 2014;89(1):99-108.
• Ma W, Liu Y, Ellison N, Shen J. Induction of C-X-C Chemokine Receptor Type 7 (CXCR7) Switches Stromal Cell-Derived Factor-1 (SDF-1) Signaling and Phagocytic Activity in Macrophages Linked to Atherosclerosis.  J Biol Chem. 2013, 288(22):15481-15494.
• Shen J, Ma W, Liu Y. Deacetylase SIRT6 Deaccelerates Endothelial Senescence. Cardiovasc Res. 2013, 97(3): 391-392.
• Ding L, Ma W, Littmann T, Camp R, Shen J. The P2Y2 Nucleotide Receptor Mediates Tissue Factor Expression in Human Coronary Artery Endothelial Cells. J Biol Chem. 2011, 286(30):27027-27038.
• Shen J, Chandrasekharan UM, Ashraf MZ, Long E, Morton RE, Liu Y, Smith JD, DiCorleto PE. Lack of MAP Kinase Phosphatase-1 Protects ApoE-null Mice against Atherosclerosis. Circ Res. 2010;106(5):902-910.
• Kinney C, Chandrasekharan UM, Yang L, Shen J, Kinter M, McDermott MS, DiCorleto PE. Histone H3 as a Novel Substrate for MAP Kinase Phosphatase-1. Am J Physiol Cell Physiol.2009;296(2):C242-249.
• Shen J and DiCorleto PE. Adenosine prompts the heart to recruit endothelial progenitors. Circ Res. 2008;102(3):280-282.
• Shen J and DiCorleto PE. ADP stimulates human endothelial cell migration via P2Y1 nucleotide receptor-mediated mitogen-activated protein kinase pathways. Circ Res. 2008;102(4):448-456.
• Shen J, Halenda SP, Sturek M, Wilden PA. Cell-signaling evidence for adenosine stimulation of coronary smooth muscle proliferation via the A1 adenosine receptor. Circ Res. 2005;97(6):574-582. [Journal cover photo, September 16, 2005].
• Shen J, Halenda SP, Sturek M, Wilden PA.  Novel mitogenic effect of adenosine on coronary artery smooth muscle cells: role for the A1 adenosine receptor. Circ Res. 2005; 96(9):982-990.
• Shen J, Seye CI, Wang M, Weisman GA, Wilden PA, Sturek M.  Cloning, up-regulation, and mitogenic role of porcine P2Y2 receptor in coronary artery smooth muscle cells. Mol Pharmacol. 2004; 66(5): 1265-1274.
• Shen J, Zheng XF, Wei EQ and Kwan CY. Green tea catechins evoke a phasic contraction in rat aorta via H2O2-mediated multiple-signaling pathways. Clin Exp Pharmacol Physiol. 2003(1-2):88-95.
• Shen J, Zheng XF, Wei EQ, Kwan CY. Evidence against sarcoplasmic reticulum Ca2+-pump inhibition as the mechanism of H2O2-induced contraction of rat aorta. Acta Pharmacol Sin.  2001;22(6):498-504.
• Shen J, Zheng XF, Kwan CY. Evidence for P2-purinoceptors contribution in H2O2-induced contraction of rat aorta in the absence of endothelium.  Cardiovasc Res  2000;47(3):574-585.
• Shen J, Zheng XF, Kwan CY. Differential contractile actions of reactive oxygen species on rat aorta: selective activation of ATP receptor by H2O2. Life Sci  2000;66(21):PL291-296.
• Shen J, Zheng XF. Characteristics of impaired endothelium-dependent relaxation of rat aorta after streptozotocin-induced diabetes. Acta Pharmacol Sin 1999;20(9):844-850.