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

Hindy, George LU ; Tyrrell, Daniel J. ; Vasbinder, Alexi ; Wei, Changli ; Presswalla, Feriel ; Wang, Hui ; Blakely, Pennelope ; Ozel, Ayse Bilge ; Graham, Sarah and Holton, Grace H. , et al. (2022) In Journal of Clinical Investigation 132(24). p.1-14
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
132
issue
24
article number
e158788
pages
1 - 14
publisher
The American Society for Clinical Investigation
external identifiers
  • pmid:36194491
  • scopus:85144516555
ISSN
0021-9738
DOI
10.1172/JCI158788
language
English
LU publication?
yes
id
d5f3a83a-3afc-47a9-afad-50412b1ec4ec
alternative location
https://www.jci.org/articles/view/158788
date added to LUP
2023-01-13 12:04:58
date last changed
2024-01-18 18:07:53
@article{d5f3a83a-3afc-47a9-afad-50412b1ec4ec,
  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       = {{Hindy, George and Tyrrell, Daniel J. and Vasbinder, Alexi and Wei, Changli and Presswalla, Feriel and Wang, Hui and Blakely, Pennelope and Ozel, Ayse Bilge and Graham, Sarah and Holton, Grace H. and Dowsett, Joseph and Fahed, Akl C. and Amadi, Kingsley-michael and Erne, Grace K. and Tekmulla, Annika and Ismail, Anis and Launius, Christopher and Sotoodehnia, Nona and Pankow, James S. and Thørner, Lise Wegner and Erikstrup, Christian and Pedersen, Ole Birger and Banasik, Karina and Brunak, Søren and Ullum, Henrik and Eugen-Olsen, Jesper and Ostrowski, Sisse Rye and Haas, Mary E. and Nielsen, Jonas B. and Lotta, Luca A. and Engström, Gunnar and Melander, Olle and Orho-Melander, Marju and Zhao, Lili and Murthy, Venkatesh L. and Pinsky, David J. and Willer, Cristen J. and Heckbert, Susan R. and Reiser, Jochen and Goldstein, Daniel R. and Desch, Karl C. and Hayek, Salim S.}},
  issn         = {{0021-9738}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{24}},
  pages        = {{1--14}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{Journal of Clinical Investigation}},
  title        = {{Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis}},
  url          = {{http://dx.doi.org/10.1172/JCI158788}},
  doi          = {{10.1172/JCI158788}},
  volume       = {{132}},
  year         = {{2022}},
}