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Increase in SuPAR Levels Promotes Atherosclerosis
Quick Takes
- High suPAR levels were strongly associated with incident CVD and accelerated atherosclerosis, as measured by serial CAC scores independent of decline in kidney function and established risk factors in a cohort of over 5,000 participants.
- Increased suPAR levels were also causally linked to atherosclerotic phenotypes in the UK Biobank, notably coronary artery disease, myocardial infarction, and peripheral arterial disease, in addition to kidney disease.
- The aggregate of epidemiologic, genetic, and experimental evidence and the advent of anti-suPAR therapies supports examining suPAR as a potential target for the prevention and treatment of CVD.
Study Questions:
Is there a causal role for soluble urokinase plasminogen activator receptor (suPAR) in cardiovascular disease (CVD)?
Methods:
The investigators assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. They performed a genome-wide association study meta-analysis for suPAR levels in over 24,000 individuals; confirming experimentally a missense variant that specifically led to higher suPAR levels and using Mendelian randomization and rare variant association to leverage the genotypes and disease phenotypes in 500,000 participants of the UK Biobank. Also, using a well-established murine model of atherosclerosis, the authors assessed whether mice overexpressing suPAR were more prone to atherosclerotic disease compared to wild-type mice, and examined its impact on monocyte profile and function.
Results:
Serum suPAR levels were found 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, the authors 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 overexpressing 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.
Conclusions:
The authors concluded that suPAR is a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.
Perspective:
This study provides epidemiologic, genetic, and experimental evidence of a causal role for suPAR in atherosclerosis. High suPAR levels were strongly associated with incident CVD and accelerated atherosclerosis, as measured by serial coronary artery calcium (CAC) scores independent of decline in kidney function and established risk factors in a cohort of over 5,000 participants. Furthermore, increased suPAR levels were causally linked to atherosclerotic phenotypes in the UK Biobank, notably coronary artery disease, myocardial infarction, and peripheral arterial disease, in addition to kidney disease. The aggregate of epidemiologic, genetic, and experimental evidence provided in this study and the advent of anti-suPAR therapies supports examining suPAR as a potential target for the prevention and treatment of CVD.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins
Keywords: Atherosclerosis, Chemotaxis, Cholesterol, Coronary Artery Disease, Dyslipidemias, Genome-Wide Association Study, Genotype, Kidney Diseases, Macrophages, Monocytes, Myocardial Infarction, Myocardial Ischemia, Peripheral Arterial Disease, Phenotype, Plaque, Atherosclerotic, Primary Prevention, Receptors, Urokinase Plasminogen Activator, Risk Factors, Transfection, Vascular Diseases
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