Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease Ying Zhou a , Peter J. Little a,b , Hang T. Ta a,c , Suowen Xu d , Danielle Kamato a,b, ⁎ a School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD 4102, Australia b Department of Pharmacy, Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou 510520, China c Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, St Lucia, QLD 4072, Australia d Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA abstract article info Available online xxxx Lysophosphatidic acid (LPA) is a collective name for a set of bioactive lipid species. Via six widely distributed G protein-coupled receptors (GPCRs), LPA elicits a plethora of biological responses, contributing to inflammation, thrombosis and atherosclerosis. There have recently been considerable advances in GPCR signaling especially recognition of the extended role for GPCR transactivation of tyrosine and serine/threonine kinase growth factor receptors. This review covers LPA signaling pathways in the light of new information. The use of transgenic and gene knockout animals, gene manipulated cells, pharmacological LPA receptor agonists and antagonists have provided many insights into the biological significance of LPA and individual LPA receptors in the progression of atherosclerosis and vascular diseases. This review provides a comprehensive presentation of LPA with the highlight of the distinct role of its receptors in cell and animal models that relate to atherosclerosis and vascular diseases, and therefore provides new opportunities to reduce the burden of cardiovascular diseases. The recent drug development strategies that target LPA signaling pathways are also included in this review. © 2019 Elsevier Inc. All rights reserved. Keywords: Lysophosphatidic acid G-protein coupled receptors Atherosclerosis G proteins β-arrestins Transactivation Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2. LPA and its production and degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3. The in vitro studies of LPA and LPARs in the vasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4. The in vivo studies of LPA and LPARs in the vasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5. The signaling pathways of LPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 6. Therapeutic implications of targeting LPA and its signaling pathways . . . . . . . . . . . . . . . . . . . . . . 0 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Pharmacology & Therapeutics xxx (2019) xxx Abbreviations: AC, adenylyl cyclase; ATX, autotaxin; cAMP, cyclic adenosine monophosphate; CVDs, cardiovascular diseases; DAG, diacylglycerol; DCs, dendritic cells; ECs, endothelial cells; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; GPCR, G protein-coupled receptor; HUVECs, human umbilical vein endothelial cells; IL-8, interleukin 8; LDL, low density lipoprotein; LPA, lysophosphatidic acid; LPAR, LPA receptor; LPP3, lipid phosphate phosphatase 3; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein-1; MCs, mast cells; MMPs, matrix metalloproteinases; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ox-LDL, oxidized-LDL; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PLC, phospholipase; PPARγ, peroxisome proliferator-activated receptor γ; PTKR, protein tyrosine kinase receptor; ROCK, Rho associated protein kinase; ROS, reactive oxygen species; S/TKR, serine/threonine kinase receptor; SMCs, smooth muscle cells; TGFBR1, TGF-β type I receptor; TGF-β, transforming growth factor β; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor α; VSMCs, vascular smooth muscle cells. ⁎ Corresponding author at: School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD 4102, Australia. E-mail address: d.kamato@uq.edu.au (D. Kamato). JPT-107404; No of Pages 13 https://doi.org/10.1016/j.pharmthera.2019.107404 0163-7258/© 2019 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Please cite this article as: Y. Zhou, P.J. Little, H.T. Ta, et al., Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis a..., Pharmacology & Therapeutics, https://doi.org/10.1016/j.pharmthera.2019.107404