Wed Oct 12 2022

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

A collaborative study conducted by researchers from the United States, Sweden, and Denmark, and published in The Journal of Clinical Investigation on October 4, 2022, sheds new light on the complex relationship between kidney disease and the heightened risk of atherosclerosis, a connection previously not well understood. The research centers on the role of the soluble urokinase plasminogen activator receptor (suPAR), a molecule linked with immune system activity and implicated in the progression of kidney disease, and its strong association with adverse cardiovascular outcomes.

The team conducted a thorough investigation revealing that elevated suPAR levels in the bloodstream serve as a predictive marker for the development of coronary artery calcification and subsequent cardiovascular events in a cohort of 5,406 participants who initially did not have known coronary disease. Through a comprehensive genome-wide association meta-analysis encompassing data from over 25,000 individuals, the researchers pinpointed a significant genetic variant in the PLAUR gene, known as rs4760. This variant was experimentally confirmed to result in higher suPAR levels.

Leveraging Mendelian randomization techniques within the UK Biobank dataset, the study demonstrated a causal relationship between genetically predicted elevated suPAR levels and the manifestation of atherosclerotic conditions. Further experimental models involving mice provided compelling evidence of suPAR’s pathogenic role in atherosclerosis. Mice engineered to overexpress suPAR (suPARTg) developed more severe atherosclerotic lesions characterized by increased macrophage infiltration and necrotic core formation, despite having cholesterol levels comparable to wild-type mice.

Before the onset of atherosclerotic changes, the aortas of suPARTg mice showed elevated secretion of CCL2, a chemokine involved in monocyte recruitment, and displayed higher monocyte counts than their wild-type counterparts. These monocytes demonstrated a pro-inflammatory profile and enhanced chemotactic activity, indicating a systemic alteration in monocyte function influenced by suPAR levels.

Jesper Eugen-Olsen, Ph.D., a senior scientist at Copenhagen University Hospital Hvidovre and the Chief Scientific Officer at ViroGates, emphasized the significance of this study. By integrating clinical data, genetic insights, and experimental findings, the research conclusively identifies suPAR as a critical pathogenic factor in cardiovascular disease, particularly highlighting its role in modulating monocyte function and contributing to the development of atherosclerosis. This comprehensive approach provides a clearer understanding of suPAR’s involvement in cardiovascular diseases and opens new avenues for targeted therapies.


published suPAR studies in leading medical journals

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