Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis
George Hindy, … , Karl C. Desch, Salim S. Hayek
George Hindy, … , Karl C. Desch, Salim S. Hayek
Published October 4, 2022
Citation Information: J Clin Invest. 2022;132(24):e158788. https://doi.org/10.1172/JCI158788.
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Research Article Cardiology

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

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.

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, on behalf of the DBDS Consortium, Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, on behalf of the Regeneron Genetics Center, 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

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Figure 4

MR phenome-wide association of genetically predicted suPAR by rs4760 with CVD and rare damaging missense variants’ impact on the odds of ischemic heart disease.

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MR phenome-wide association of genetically predicted suPAR by rs4760 wit...
(A) Causal effect of suPAR on 13 CVDs by MR using missense variant rs4760 as instrument. Effect estimates are provided per 1 SD increase in suPAR levels. P values were adjusted using the false discovery rate method. (B) Rare variant gene collapsing analysis of the more than 280,000 exomes in the UK Biobank. Both rare protein truncating variants and rare damaging missense variants in the PLAUR gene were selected to study the impact of attenuated PLAUR function on coronary heart disease.