Anti-Inflammatory Lipid Mediators from Polyunsaturated Fatty Acids: Insights into their Role in Atherosclerosis...

Inflammation has become a major residual risk factor for atherosclerotic cardiovascular disease (ASCVD). Certain lipid mediators, known as specialized proresolving mediators (SPMs), are mainly derived from polyunsaturated fatty acids (PUFAs) and can promote inflammation resolution while maintaining host autoimmunity. This review investigates the synthesis and ligand action pathways of these lipid mediators, as well as their regulatory mechanisms in the microenvironment of atherosclerotic plaques. Furthermore, it explores their clinical therapeutic potential, aiming to offer new insights into novel anti-inflammatory drug targets for the treatment of ASCVD.

Reduced levels of SPMs are associated with the progression of atherosclerosis. SPMs inhibit inflammatory responses in the plaque microenvironment by limiting immune cell infiltration, reducing oxidative stress, and promoting the clearance of apoptotic cells, all of which contribute to plaque stabilization. Tyrosine-protein kinase Mer (MerTK), TRIF-related adaptor molecule (TRAM), and high mobility group box 1 (HMGB1) play crucial roles in the modulation of SPM production. Clinical use of ω-3 PUFAs has been shown to reduce the incidence of fatal cardiovascular events. Furthermore, aspirin not only initiates the synthesis of specific SPMs but also extends their activity within the body. The enhanced production of SPMs promotes inflammation resolution in the plaque microenvironment without inducing immunosuppression. This characteristic highlights MerTK, TRAM, and HMGB1 as potential targets for the development of anti-inflammatory drugs. Investigating targets and compounds that enhance the production of SPMs presents a promising strategy for developing future anti-inflammatory agents.