Clinical, genetic, and experimental increase in soluble urokinase plasminogen activator receptor levels promotes atherosclerosis
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Clinical, genetic, and experimental increase in soluble urokinase plasminogen activator receptor levels promotes atherosclerosis. / Hindy, George; Tyrrell, Daniel J; Vasbinder, Alexi; Wei, Changli; Presswalla, Feriel; Wang, Hui; Blakely, Pennelope K; Ozel, Ayse Bilge; Graham, Sarah E; Holton, Grace H; Dowsett, Joseph; Fahed, Akl C; Amadi, Kingsley-Michael; Erne, Grace K; Tekumulla, Annika; Ismail, Anis; Launius, Christopher; Sotoodehnia, Nona; Pankow, James S; Thørner, Lise Wegner; Erikstrup, Christian; Pedersen, Ole Birger; Banasik, Karina; Brunak, Søren; Ullum, Henrik; Eugen-Olsen, Jesper; Ostrowski, Sisse Rye; Haas, Mary E; Nielsen, Jonas B; Lotta, Luca A; Engström, Gunnar; Melander, Olle; Orho-Melander, Marju; Zhao, Lili; Murthy, Venkatesh L; Pinsky, David J; Willer, Cristen J; Heckbert, Susan R; Reiser, Jochen; Goldstein, Daniel R; Desch, Karl C; Hayek, Salim S.
In: Journal of Clinical Investigation, Vol. 132, No. 24, e158788, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Clinical, genetic, and experimental increase in soluble urokinase plasminogen activator receptor levels promotes atherosclerosis
AU - Hindy, George
AU - Tyrrell, Daniel J
AU - Vasbinder, Alexi
AU - Wei, Changli
AU - Presswalla, Feriel
AU - Wang, Hui
AU - Blakely, Pennelope K
AU - Ozel, Ayse Bilge
AU - Graham, Sarah E
AU - Holton, Grace H
AU - Dowsett, Joseph
AU - Fahed, Akl C
AU - Amadi, Kingsley-Michael
AU - Erne, Grace K
AU - Tekumulla, 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
PY - 2022
Y1 - 2022
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 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, Pcsk9 transfection in mice over-expressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared to wild-type mice, despite similar cholesterol levels. Pre-atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared to wild-type aortas. Aortic and circulating suPARTg monocytes exhibited a pro-inflammatory 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 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, Pcsk9 transfection in mice over-expressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared to wild-type mice, despite similar cholesterol levels. Pre-atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared to wild-type aortas. Aortic and circulating suPARTg monocytes exhibited a pro-inflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.
U2 - 10.1172/JCI158788
DO - 10.1172/JCI158788
M3 - Journal article
C2 - 36194491
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 24
M1 - e158788
ER -
ID: 321783724