Unraveling the immunological roles of serum amyloid A3 in aortic immune cell subsets during atherosclerosis progression

Atherosclerosis is a growing concern in developed nations, necessitating the identification of therapeutic targets for advancing personalized medicine. Serum amyloid A3 (Saa3) has been linked to accelerated plaque progression by affecting cholesterol metabolism and modulation of inflammation. We hypothesize that knocking out Saa3 (Saa3-/-) could mitigate plaque development by regulating aortic immune cell subsets during atherosclerosis progression. Using a murine model, we induced atherosclerosis via a gain-of-function mutant PCSK9-encoding adeno-associated viral vector (AAVmPCSK9) in wild-type (WT) and Saa3-/- mice. Single-cell RNA sequencing revealed that Saa3-/- mice developed smaller plaques than WT mice, with significant differences in aortic immune cell populations, particularly aortic macrophages. Saa3-/- macrophages, characterized by high Gpnmb, Lpl, and Spp1 expressions, predominated over the typical resident foamy macrophages in WT mice. Saa3-/- mice also showed enhanced intercellular immune communication and increased signaling interactions, suggesting a shift towards an anti-inflammatory and tissue-repairing phenotype. Our study highlights the potential of Saa3 as a therapeutic target for atherosclerosis.