Serum amyloid A3 deficiency modulates aortic immune composition and attenuates murine 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 compositions during atherosclerosis progression. Using a murine model, we induced atherosclerosis via a gain-of-function mutant PCSK9-encoding adeno-associated viral vector (AAVmPCSK9) in female wild-type (WT) and Saa3 ^−/− mice. Saa3 ^−/− mice developed smaller plaques than WT mice, and single-cell RNA sequencing revealed significant differences in aortic immune cell populations, particularly among aortic macrophages. Aortic macrophages in atherosclerotic Saa3 ^−/− mice represent an anti-inflammatory and tissue-repairing phenotype and the Trem2 ^hi macrophages, characterized by high Gpnmb , Lpl , and Spp1 expressions, predominated over the typical foamy macrophages in Saa3 ^−/− compared to WT mice. Notably, SAA3 regulates cholesterol metabolism and inflammatory responses in foamy macrophages. Our study highlights Saa3 as a key modulator of aortic immune cells that impact atherosclerosis progression.