Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 24, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI158788
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Funding
- National Heart, Lung, and Blood Institute (NHLBI) [R01HL153384]
- Michigan Institute for Clinical & Health Research (MICHR) Pilot Grant Program [UL1TR002240]
- Gilead Sciences Research Scholar Program in Cardiovascular Disease
- NHLBI [R01HL153384, T32-HL007853, N02-HL-64278]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK128012]
- NIH [R01HL153384, R01HL141399, R01AG028082, R35HL155169]
- Independent Research Fund [0602-02634B]
- Novo Nordisk Foundation [NNF17OC0027594, NNF14CC0001]
- Bio- and Genome Bank Denmark
- A.P. Moller Fonden. Aase og Ejnar Danielsens Fond [10- 001356]
- MESA investigators
- MESA [75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC- 95164, 75N92020D00007]
- The MESA [N01HC- 95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, DK063491, N01HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168]
- Common Fund of the Office of the Director of the NIH
- National Cancer Institute (NCI)
- National Human Genome Research Institute (NHGRI)
- National Institute on Drug Abuse (NIDA)
- National Institute of Mental Health (NIMH)
- National Institute of Neurological Disorders and Stroke (NINDS)
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This study investigated the pathogenic involvement of soluble urokinase plasminogen activator receptor (suPAR) in atherosclerosis. The researchers found that suPAR levels were predictive of coronary artery calcification and cardiovascular events. Through genetic analysis and experimental models, they identified a variant in the PLAUR gene that led to higher suPAR levels and confirmed a causal association between suPAR levels and atherosclerotic phenotypes. The study also found that suPAR affected monocyte function, leading to increased inflammation and chemotaxis.
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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