Abstract Body (Do not enter title and authors here): Introduction:
Chronic inflammation is a major component of atherosclerosis. Soluble urokinase plasminogen activator receptor (suPAR) is a regulator of innate immune activity, which over-expression in mice led to accelerated atherosclerosis and modulation of myeloid cell function. We sought to determine whether the human form of suPAR would similarly promote atherosclerosis.
Methods:
We induced atherosclerosis in a murine model overexpressing human suPAR and Wild-type mice using proprotein convertase subilisin/kexin-9 (PCSK9) transfection and 42% high fat diet for 10 weeks. We then analyzed atherosclerotic lesion histology and size using immunohistochemistry. We also compared the impact of human suPAR (2.5 and 10 ng/ml) to vehicle on human derived macrophages on polarization markers and cytokine production using flow cytometry and multiplex fluorescent immunoassays, for 24 hours. Lastly, we measured the phagocytic ability of human derived macrophages of oxidized-LDL (ox-LDL) following treatment with increasing human suPAR concentrations 1, 5 and 10 ng/ml.
Results:
Human suPAR over-expressing mice had substantially increased atherosclerotic plaques compared with those in WT mice. Mechanistically, exposure human suPAR activates human derived macrophages as evidence by up-regulation of polarization markers (CD80) and increased secretion of pro-inflammatory chemokines (CCL2, CX3CL1, IFN-gamma) (p<0.01). Consistently, human macrophages treated with 10ng/ml suPAR had 1.5-fold decreased ability to engulf ox-LDL (P<0.05).
Conclusion:
These findings provide further support for suPAR’s role as a pathogenic factor for atherosclerosis that modulates macrophages function – cells central to the development and progression of the disease. Targeting suPAR-mediated pathways may offer potential therapeutic strategies for mitigating chronic inflammation and reducing the burden of atherosclerotic cardiovascular disease.