Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis

George Hindy; Daniel J. Tyrrell; Alexi Vasbinder; Changli Wei; Feriel Presswalla; Hui Wang; Pennelope Blakely; Ayse Bilge Ozel; Sarah Graham; Grace H. Holton; Joseph Dowsett; Akl C. Fahed; Kingsley Michael Amadi; Grace K. Erne; Annika Tekmulla; Anis Ismail; Christopher Launius; Nona Sotoodehnia; James S. Pankow; Lise Wegner Thørner; Christian Erikstrup; Ole Birger Pedersen; Karina Banasik; Søren Brunak; Henrik Ullum; Jesper Eugen-Olsen; Sisse Rye Ostrowski; Mary E. Haas; Jonas B. Nielsen; Luca A. Lotta; Gunnar Engström; Olle Melander; Marju Orho-Melander; Lili Zhao; Venkatesh L. Murthy; David J. Pinsky; Cristen J. Willer; Susan R. Heckbert; Jochen Reiser; Daniel R. Goldstein; Karl C. Desch; Salim S. Hayek

doi:10.1172/JCI158788

Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis

George Hindy, Daniel J. Tyrrell, Alexi Vasbinder, Changli Wei, Feriel Presswalla, Hui Wang, Pennelope Blakely, Ayse Bilge Ozel, Sarah Graham, Grace H. Holton, Joseph Dowsett, Akl C. Fahed, Kingsley Michael Amadi, Grace K. Erne, Annika Tekmulla, Anis Ismail, Christopher Launius, Nona Sotoodehnia, James S. Pankow, Lise Wegner ThørnerChristian Erikstrup, Ole Birger Pedersen, Karina Banasik, Søren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, Gunnar Engström, Olle Melander, Marju Orho-Melander, Lili Zhao, Venkatesh L. Murthy, David J. Pinsky, Cristen J. Willer, Susan R. Heckbert, Jochen Reiser, Daniel R. Goldstein, Karl C. Desch, Salim S. Hayek

Epidemiology & Community Health

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

Original language	English (US)
Article number	e158788
Journal	Journal of Clinical Investigation
Volume	132
Issue number	24
DOIs	https://doi.org/10.1172/JCI158788
State	Published - Dec 15 2022

Bibliographical note

Funding Information:
The study was funded by National Heart, Lung, and Blood Institute (NHLBI) R01HL153384, the Michigan Institute for Clinical & Health Research (MICHR) Pilot Grant Program (UL1TR002240), and the Gilead Sciences Research Scholar Program in Cardiovascular Disease. SSH is supported by NHLBI R01HL153384, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01-DK128012, and the Gilead Sciences Research Scholar Program in Cardiovascular Disease. KCD is supported by NIH R01HL141399 and R01HL153384. DRG is supported by NIH R01AG028082 and R35HL155169. AV is supported by NHLBI T32-HL007853. DBDS was funded by the Independent Research Fund (0602-02634B) and The Novo Nordisk Foundation (NNF17OC0027594 and NNF-14CC0001), Bio-and Genome Bank Denmark, A.P. Møller Fonden. Aase og Ejnar Danielsens Fond (10-001356) MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix and the Broad Institute of MIT and Harvard using the Affymetrix Genome-Wide Human SNP Array, version 6.0. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. We thank the participants of the GABC, TSS, MESA, MDC, DBDS, and UK Biobank cohorts for their contributions to advancing scientific knowledge. The GTEx Project was supported by the Common Fund of the Office of the Director of the NIH, and by the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI), NHLBI, the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from the GTEx portal on 06/01/22. We thank Andrea Obi and Sriganesh Sharma for their feedback and suggestions on interpretation of the findings. We thank Maggie Ginter-Frankovitch for her assistance in performing in vivo and in vitro experiments for this study. See Supplemental Acknowledgments for details on the DBDS Consortium and the Regeneron Genetics Center.

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© 2022, Hindy et al.

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Hindy, G., Tyrrell, D. J., Vasbinder, A., Wei, C., Presswalla, F., Wang, H., Blakely, P., Ozel, A. B., Graham, S., Holton, G. H., Dowsett, J., Fahed, A. C., Michael Amadi, K., Erne, G. K., Tekmulla, A., Ismail, A., Launius, C., Sotoodehnia, N., Pankow, J. S., ... Hayek, S. S. (2022). Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis. Journal of Clinical Investigation, 132(24), Article e158788. https://doi.org/10.1172/JCI158788

Hindy, G, Tyrrell, DJ, Vasbinder, A, Wei, C, Presswalla, F, Wang, H, Blakely, P, Ozel, AB, Graham, S, Holton, GH, Dowsett, J, Fahed, AC, Michael Amadi, K, Erne, GK, Tekmulla, A, Ismail, A, Launius, C, Sotoodehnia, N, Pankow, JS, Thørner, LW, Erikstrup, C, Pedersen, OB, Banasik, K, Brunak, S, Ullum, H, Eugen-Olsen, J, Ostrowski, SR, Haas, ME, Nielsen, JB, Lotta, LA, Engström, G, Melander, O, Orho-Melander, M, Zhao, L, Murthy, VL, Pinsky, DJ, Willer, CJ, Heckbert, SR, Reiser, J, Goldstein, DR, Desch, KC & Hayek, SS 2022, 'Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis', Journal of Clinical Investigation, vol. 132, no. 24, e158788. https://doi.org/10.1172/JCI158788

@article{3e70aeaeff6548459b6a120e139760bb,

title = "Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis",

abstract = "People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.",

author = "George Hindy and Tyrrell, {Daniel J.} and Alexi Vasbinder and Changli Wei and Feriel Presswalla and Hui Wang and Pennelope Blakely and Ozel, {Ayse Bilge} and Sarah Graham and Holton, {Grace H.} and Joseph Dowsett and Fahed, {Akl C.} and {Michael Amadi}, Kingsley and Erne, {Grace K.} and Annika Tekmulla and Anis Ismail and Christopher Launius and Nona Sotoodehnia and Pankow, {James S.} and Th{\o}rner, {Lise Wegner} and Christian Erikstrup and Pedersen, {Ole Birger} and Karina Banasik and S{\o}ren Brunak and Henrik Ullum and Jesper Eugen-Olsen and Ostrowski, {Sisse Rye} and Haas, {Mary E.} and Nielsen, {Jonas B.} and Lotta, {Luca A.} and Gunnar Engstr{\"o}m and Olle Melander and Marju Orho-Melander and Lili Zhao and Murthy, {Venkatesh L.} and Pinsky, {David J.} and Willer, {Cristen J.} and Heckbert, {Susan R.} and Jochen Reiser and Goldstein, {Daniel R.} and Desch, {Karl C.} and Hayek, {Salim S.}",

note = "Funding Information: The study was funded by National Heart, Lung, and Blood Institute (NHLBI) R01HL153384, the Michigan Institute for Clinical & Health Research (MICHR) Pilot Grant Program (UL1TR002240), and the Gilead Sciences Research Scholar Program in Cardiovascular Disease. SSH is supported by NHLBI R01HL153384, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01-DK128012, and the Gilead Sciences Research Scholar Program in Cardiovascular Disease. KCD is supported by NIH R01HL141399 and R01HL153384. DRG is supported by NIH R01AG028082 and R35HL155169. AV is supported by NHLBI T32-HL007853. DBDS was funded by the Independent Research Fund (0602-02634B) and The Novo Nordisk Foundation (NNF17OC0027594 and NNF-14CC0001), Bio-and Genome Bank Denmark, A.P. M{\o}ller Fonden. Aase og Ejnar Danielsens Fond (10-001356) MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix and the Broad Institute of MIT and Harvard using the Affymetrix Genome-Wide Human SNP Array, version 6.0. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. We thank the participants of the GABC, TSS, MESA, MDC, DBDS, and UK Biobank cohorts for their contributions to advancing scientific knowledge. The GTEx Project was supported by the Common Fund of the Office of the Director of the NIH, and by the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI), NHLBI, the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from the GTEx portal on 06/01/22. We thank Andrea Obi and Sriganesh Sharma for their feedback and suggestions on interpretation of the findings. We thank Maggie Ginter-Frankovitch for her assistance in performing in vivo and in vitro experiments for this study. See Supplemental Acknowledgments for details on the DBDS Consortium and the Regeneron Genetics Center. Publisher Copyright: {\textcopyright} 2022, Hindy et al.",

year = "2022",

month = dec,

day = "15",

doi = "10.1172/JCI158788",

language = "English (US)",

volume = "132",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "24",

}

TY - JOUR

T1 - Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis

AU - Hindy, George

AU - Tyrrell, Daniel J.

AU - Vasbinder, Alexi

AU - Wei, Changli

AU - Presswalla, Feriel

AU - Wang, Hui

AU - Blakely, Pennelope

AU - Ozel, Ayse Bilge

AU - Graham, Sarah

AU - Holton, Grace H.

AU - Dowsett, Joseph

AU - Fahed, Akl C.

AU - Michael Amadi, Kingsley

AU - Erne, Grace K.

AU - Tekmulla, Annika

AU - Ismail, Anis

AU - Launius, Christopher

AU - Sotoodehnia, Nona

AU - Pankow, James S.

AU - Thørner, Lise Wegner

AU - Erikstrup, Christian

AU - Pedersen, Ole Birger

AU - Banasik, Karina

AU - Brunak, Søren

AU - Ullum, Henrik

AU - Eugen-Olsen, Jesper

AU - Ostrowski, Sisse Rye

AU - Haas, Mary E.

AU - Nielsen, Jonas B.

AU - Lotta, Luca A.

AU - Engström, Gunnar

AU - Melander, Olle

AU - Orho-Melander, Marju

AU - Zhao, Lili

AU - Murthy, Venkatesh L.

AU - Pinsky, David J.

AU - Willer, Cristen J.

AU - Heckbert, Susan R.

AU - Reiser, Jochen

AU - Goldstein, Daniel R.

AU - Desch, Karl C.

AU - Hayek, Salim S.

N1 - Funding Information: The study was funded by National Heart, Lung, and Blood Institute (NHLBI) R01HL153384, the Michigan Institute for Clinical & Health Research (MICHR) Pilot Grant Program (UL1TR002240), and the Gilead Sciences Research Scholar Program in Cardiovascular Disease. SSH is supported by NHLBI R01HL153384, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01-DK128012, and the Gilead Sciences Research Scholar Program in Cardiovascular Disease. KCD is supported by NIH R01HL141399 and R01HL153384. DRG is supported by NIH R01AG028082 and R35HL155169. AV is supported by NHLBI T32-HL007853. DBDS was funded by the Independent Research Fund (0602-02634B) and The Novo Nordisk Foundation (NNF17OC0027594 and NNF-14CC0001), Bio-and Genome Bank Denmark, A.P. Møller Fonden. Aase og Ejnar Danielsens Fond (10-001356) MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix and the Broad Institute of MIT and Harvard using the Affymetrix Genome-Wide Human SNP Array, version 6.0. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. We thank the participants of the GABC, TSS, MESA, MDC, DBDS, and UK Biobank cohorts for their contributions to advancing scientific knowledge. The GTEx Project was supported by the Common Fund of the Office of the Director of the NIH, and by the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI), NHLBI, the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from the GTEx portal on 06/01/22. We thank Andrea Obi and Sriganesh Sharma for their feedback and suggestions on interpretation of the findings. We thank Maggie Ginter-Frankovitch for her assistance in performing in vivo and in vitro experiments for this study. See Supplemental Acknowledgments for details on the DBDS Consortium and the Regeneron Genetics Center. Publisher Copyright: © 2022, Hindy et al.

PY - 2022/12/15

Y1 - 2022/12/15

N2 - People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

AB - People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

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VL - 132

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

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ER -

Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis

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