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Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis
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- Hindy, George (author)
- Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups,Broad Institute,Qatar University
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- Tyrrell, Daniel J. (author)
- University of Michigan
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- Vasbinder, Alexi (author)
- University of Michigan
- show more...
- Fahed, Akl C. (author)
- Amadi, Kingsley-michael (author)
- Erne, Grace K. (author)
- Tekmulla, Annika (author)
- Ismail, Anis (author)
- Launius, Christopher (author)
- Sotoodehnia, Nona (author)
- Pankow, James S. (author)
- Thørner, Lise Wegner (author)
- Erikstrup, Christian (author)
- Pedersen, Ole Birger (author)
- Banasik, Karina (author)
- Brunak, Søren (author)
- Ullum, Henrik (author)
- Eugen-Olsen, Jesper (author)
- Ostrowski, Sisse Rye (author)
- Haas, Mary E. (author)
- Nielsen, Jonas B. (author)
- Lotta, Luca A. (author)
- Zhao, Lili (author)
- Murthy, Venkatesh L. (author)
- Pinsky, David J. (author)
- Willer, Cristen J. (author)
- Heckbert, Susan R. (author)
- Reiser, Jochen (author)
- Goldstein, Daniel R. (author)
- Desch, Karl C. (author)
- Hayek, Salim S. (author)
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- (creator_code:org_t)
- 2022
- 2022
- English.
- In: Journal of Clinical Investigation. - 0021-9738. ; 132:24, s. 1-14
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
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- ref (subject category)
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