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

Area of Science:

• Cardiovascular Research
• Nephrology
• Immunology

Background:

• Kidney disease patients have higher atherosclerosis rates, with soluble urokinase plasminogen activator receptor (suPAR) linked to cardiovascular outcomes.
• The precise role of suPAR in atherosclerosis pathogenesis remains unclear.

Approach:

• Epidemiologic, genetic, and experimental methods were used to investigate suPAR's involvement in atherosclerosis.
• Serum suPAR levels predicted coronary artery calcification and cardiovascular events in a cohort of 5,406 individuals.
• A genome-wide association meta-analysis identified a PLAUR gene variant (rs4760) associated with elevated suPAR levels.

Key Points:

• Mendelian randomization indicated a causal link between genetically predicted suPAR and atherosclerotic phenotypes.
• suPAR-overexpressing mice (suPARTg) exhibited significantly larger atherosclerotic plaques with necrotic cores and macrophage infiltration.
• suPARTg mice showed increased aortic CCL2 excretion, higher monocyte counts, and enhanced monocyte proinflammatory profiles and chemotaxis.

Conclusions:

• suPAR is a pathogenic factor in atherosclerosis, partly by modulating monocyte function.
• These findings highlight suPAR as a potential therapeutic target for cardiovascular complications in kidney disease.