Abstract
Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet phenotypes and cardiovascular disease in humans, as determined by Mendelian Randomization. Targeting this receptor-ligand interaction may be a viable therapeutic strategy to treat or prevent cardiovascular and thrombotic disease.
| Original language | English |
|---|---|
| Article number | 850 |
| Journal | Nature communications |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
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In: Nature communications, Vol. 14, No. 1, 850, 12.2023.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - SVEP1 is an endogenous ligand for the orphan receptor PEAR1
AU - Elenbaas, Jared S.
AU - Pudupakkam, Upasana
AU - Ashworth, Katrina J.
AU - Kang, Chul Joo
AU - Patel, Ved
AU - Santana, Katherine
AU - Jung, In Hyuk
AU - Lee, Paul C.
AU - Burks, Kendall H.
AU - Amrute, Junedh M.
AU - Mecham, Robert P.
AU - Halabi, Carmen M.
AU - Aliso, Arturo
AU - Di Paola, Jorge
AU - Stitziel, Nathan O.
N1 - Funding Information: We thank Dr. Bruce Carter from Vanderbilt University for providing Pear1-/-mice. We thank the Washington University School of Medicine diabetes research center mouse phenotyping core for their help with the metabolic phenotyping. The expert technical assistance of Petra Erdmann-Gilmore, Dr. Yiling Mi and Rose Connors is gratefully acknowledged. The proteomic experiments were performed at the Washington University Proteomics Shared Resource (WU-PSR), R Reid Townsend MD, PhD (Director), Robert Sprung, PhD (Co-Director), Qiang Zhang, PhD (Co-Director). The WU-PSR is supported in part by the WU Institute of Clinical and Translational Sciences (NCATS UL1TR000448), the Mass Spectrometry Research Resource (NIGMS P41GM103422; R24GM136766) and the Siteman Comprehensive Cancer Center Support Grant (NCI P30CA091842). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/20/21. We thank Professor Adam Butterworth for assistance in obtaining access to the individual level data from the INTERVAL pQTL GWAS study. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource [http://bioresource.nihr.ac.uk] and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. The INTERVAL study was funded by NHSBT (11-01-GEN). The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. Proteomic assays were funded by the academic coordinating centre for INTERVAL and MRL, Merck & Co., Inc. A complete list of the investigators and contributors to the INTERVAL trial is provided elsewhere83. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This work was supported in part by grants from the National Institutes of Health (NIH) to JSE (T32GM007200, T32HL134635, and F30HL152521), CMH (K08HL135400), NOS (R01HL159171, R01HL131961, UM1HG008853, and P01HL151328), by the Longer Life Foundation: A RGA/Washington University Collaboration (LLF 2021-007 to NOS), by the Missouri ACC and the Missouri ACC Foundation (NOS), by the Foundation for Barnes-Jewish Hospital (NOS), and by the Diabetes Research Center at Washington University under NIH award number P30DK020579. Proteomic assays were funded in part by the Washington University Institute of Clinical and Translational Science under NIH award number UL1TR002345. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Dr. Bruce Carter from Vanderbilt University for providing Pear1 mice. We thank the Washington University School of Medicine diabetes research center mouse phenotyping core for their help with the metabolic phenotyping. The expert technical assistance of Petra Erdmann-Gilmore, Dr. Yiling Mi and Rose Connors is gratefully acknowledged. The proteomic experiments were performed at the Washington University Proteomics Shared Resource (WU-PSR), R Reid Townsend MD, PhD (Director), Robert Sprung, PhD (Co-Director), Qiang Zhang, PhD (Co-Director). The WU-PSR is supported in part by the WU Institute of Clinical and Translational Sciences (NCATS UL1TR000448), the Mass Spectrometry Research Resource (NIGMS P41GM103422; R24GM136766) and the Siteman Comprehensive Cancer Center Support Grant (NCI P30CA091842). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/20/21. We thank Professor Adam Butterworth for assistance in obtaining access to the individual level data from the INTERVAL pQTL GWAS study. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England ( www.nhsbt.nhs.uk ), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource [ http://bioresource.nihr.ac.uk ] and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. The INTERVAL study was funded by NHSBT (11-01-GEN). The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. Proteomic assays were funded by the academic coordinating centre for INTERVAL and MRL, Merck & Co., Inc. A complete list of the investigators and contributors to the INTERVAL trial is provided elsewhere. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This work was supported in part by grants from the National Institutes of Health (NIH) to JSE (T32GM007200, T32HL134635, and F30HL152521), CMH (K08HL135400), NOS (R01HL159171, R01HL131961, UM1HG008853, and P01HL151328), by the Longer Life Foundation: A RGA/Washington University Collaboration (LLF 2021-007 to NOS), by the Missouri ACC and the Missouri ACC Foundation (NOS), by the Foundation for Barnes-Jewish Hospital (NOS), and by the Diabetes Research Center at Washington University under NIH award number P30DK020579. Proteomic assays were funded in part by the Washington University Institute of Clinical and Translational Science under NIH award number UL1TR002345. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. -/- Publisher Copyright: © 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet phenotypes and cardiovascular disease in humans, as determined by Mendelian Randomization. Targeting this receptor-ligand interaction may be a viable therapeutic strategy to treat or prevent cardiovascular and thrombotic disease.
AB - Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet phenotypes and cardiovascular disease in humans, as determined by Mendelian Randomization. Targeting this receptor-ligand interaction may be a viable therapeutic strategy to treat or prevent cardiovascular and thrombotic disease.
UR - http://www.scopus.com/inward/record.url?scp=85148114769&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-36486-0
DO - 10.1038/s41467-023-36486-0
M3 - Article
C2 - 36792666
AN - SCOPUS:85148114769
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 850
ER -