Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis
Year: 2022
Type: article
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.
DOI: 10.1172/jci158788
Authors: 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
Institutions: Broad Institute, Lund University, Qatar University, Massachusetts Institute of Technology, University of Michigan, Michigan Medicine, Rush University Medical Center, Copenhagen University Hospital, University of Washington, University of Minnesota, Aarhus University Hospital, Zealand University Hospital Køge, University of Copenhagen, Novo Nordisk Foundation, Statens Serum Institut, Hvidovre Hospital, Regeneron (United States)
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Gilead Sciences, Gilead Foundation, Regeneron Pharmaceuticals, Broad Institute, Aase og Ejnar Danielsens Fond, Novo Nordisk, A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal, Novo Nordisk Fonden, National Institutes of Health, Michigan Institute for Clinical and Health Research, Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Common Fund
Awards: G1028935811, G1083745640, G1122870748, G1200636938, G1261793039, MESA, G1269631540, G1276754516, G1373328648, G1412221515, G143460415, G1462415530, G1539384734, G1640378483, G1686417863, G1803853571, G1931912876, G2040478069, G2144938473, G2169623015, G22458031, G2248434558, G2262782284, G2290386743, G2326437104, G2334180555, MESA, G2507118478, G2580996367, G2803000934, MESA, G2837638605, G290884426, G291913881, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, G297113894, G303055330, G3093995152, G3342643523, G343705321, G3568487487, G3570589137, G3647016462, G3676546685, G3687594596, G36937976, G370977179, G3803894709, MESA, G3943721533, G3990748671, G399481048, G4010488941, G40762112, G4086764833, Mechanisms of dysregulated immunity with aging, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), G4312169524, Extracorporeal SuPAR Extraction to Prevent COVID-19-associated Acute Kidney Injury, G4512137732, G4563812999, G4653673457, G467313275, G4688346656, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, G4887378724, G4922938341, MESA, G5088122703, G5108002584, G514410172, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, G55907201, G5654179670, G5755700318, G5787256936, G5850737185, G591338366, G6095866717, G6130894301, Cerebrovascular Mitochondrial Function in Aging and Ischemic Injury, G6359107525, G6398255701, Institute for Clinical and Translational Research, MESA, G6430168774, G6514094751, G6541715359, G6580025376, G66341962, G6705412177, SNP HEALTH ASSOCIATION RESOURCE (SHARE), G6742279884, Physician Scientist Training in Age-Related Diseases, G6798586005, G6971475997, G7007046788, Cerebrovascular Mitochondrial Function in Aging and Ischemic Injury, MESA, G7462069030, G7495086035, Novel mechanisms of age-enhanced vasculopathy after heart transplantation, G78770644, G7953181477, Clinical and Translational Science Award, G829705748, G842756795, G8647020749, G8736382857, G8761005068, G8852914737, G9000004549, G9000004784, G9000006353, G9000013477, G9000014989, G9000017360, G9000019818, G9000025517, G9000031392, G9000038858, G9000050004, G9000063950, G9000065698, G9000099314, G9000140433, G9000197285, G9000301995, Diabetes Research Center (DRC), Integrating genomic and nongenomic risk for coronary artery disease, G94668252, G991334795, G996161988
OpenAlex ID: W4301178755