Complement Factor H and Pro-Resolving Mediators Synergistically Enhance Plaque Stability in Peripheral Arterial Disease

Background Inflammation is a key driver of plaque rupture and adverse cardiovascular events in atherosclerosis patients. However, accurate identification of high-risk individuals in preventative cardiology has remained elusive. Methods In this study we analyzed the biochemical characteristics of high-density lipoproteins (HDL), plasma metabololipidomics and atherosclerotic plaques obtained from peripheral artery disease patients. This included the measurements of circulating complement activation markers, complement factor H-associated HDL, malondialdehyde modified HDL, plasma lipid mediators, as well as analyzing the HDL and plaque proteome. In addition, arterial plaques were subjected to histological and immunofluorescence staining. Results We identified novel pro- and anti-inflammatory molecules and structural components of arterial plaques indicative of plaque stability. An increase in HDL-associated complement regulatory protein factor H correlated with higher levels of specialized pro-resolving lipid mediators, changes in plaque calcification, and specific extracellular matrix proteins. The presence of factor H in HDL was associated with increased cholesterol efflux supporting its role in HDL’s antiatherogenic effects. Conclusions Our findings indicate that complement regulation and pro-resolving responses work synergistically to exert anti-inflammatory effects, which are essential for maintaining extracellular matrix integrity. These findings may assist in early detection of high-risk cardiovascular disease and optimize therapeutic strategies to prevent adverse events.