Abstract 416: Are Good and Evil Polarized? - How Murine Rgs5 knock-out Influences Macrophage Polarization and Aortic Atherosclerosis and Dissection

Abstract

Background: Aortic atherosclerosis and dissection cause significant morbidity and mortality. Although atherosclerosis is associated with aortic dissection, points of interaction are unclear. Regulator-of-G-protein signaling 5 (RGS5) is still insufficiently characterized regarding its role in aortic atherosclerosis and dissection. Objectives: We investigated Rgs5-deficiencie’s effects on aortic atherosclerosis and dissection. Methods: ApoE -/- Rgs5 GFP/GFP double knockout mice (rraa, n=15) and WT littermates (RRaa, n=17) were fed a cholesterol-rich diet for 14weeks. Plaque size, plaque morphology (composition and a validated vulnerability score based on Stary criteria), macrophage phenotype and aortic dissection were evaluated. Results: rraa mice displayed more aortic dissections (5/15) compared to WT (0/17; p<0.05 in Chi 2 -test). Surprisingly, rraa showed significantly smaller (rraa plaque size 190 657 μm 2 ± 93184 vs. control 398 279 μm 2 ± 153339) and less complicated plaques (5 of 15 mice with >2 vulnerability features) compared to RRaa (14 of 15 with >2 vulnerability features, p<0.01). While relative areas of aSMA and lipids did not differ between genotypes, relative plaque areas positive for collagen and CD45 were increased in rraa (n=15/17, p<0.01) compared to RRaa. Due to smaller plaque sizes were anti-inflammatory macrophages reduced and pro-inflammatory macrophages increased in absolute numbers (p<0.05). Phenotyping of CD45 + -myeloid cells revealed increased proportions of macrophages staining positive for pro-inflammatory markers (Cd86/Cd45: 24.71 area% ± 3.75 for RRaa; 60.95 area% ± 5.909, for rraa and iNOS/Cd45: 37.22 area% ± 6.37, for RRaa; 73.99 area% ± 3.997 for rraa, p<0.01), while anti-inflammatory markers (Cd163/Cd45 and Dectin/Cd45 double stainings) remained unchanged. Conclusions: rraa mice are more prone to aortic dissection despite smaller and less complex plaques with reduced anti-inflammatory but increased numbers of pro-inflammatory macrophages. We hypothesize that pro-inflammatory macrophage polarization along with evasion of anti-inflammatory macrophages in rraa mice could be causative for higher dissection numbers. Our data warrant further studies into the diverging pathomechanistic roles of Rgs5 in aortic dissection and atherosclerosis.