Abstract
Background: There is growing evidence that monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis crucially affects the initiation and progression of abdominal aortic aneurysm (AAA). We hypothesize that inhibition of CCR2 may prevent AAA inflammation and rupture. Methods: 40 Male and 49 female Sprague-Dawley rats underwent intraluminal infrarenal abdominal aortic exposure to elastase to induce AAA. Rats received daily β-aminopropionitrile to promote AAA rupture. On post-operative day 3 (POD3), a treatment group (15 males, 17 females) received daily oral gavage of a CCR2 inhibitor (CCR2i; RS-504393), and a control group (25 males, 32 females) received no CCR2i. On POD6, both groups underwent PET/CT with a CCR2 targeting radiotracer 64 Cu-DOTA-ECL1i. In addition, AAA tissue cytokine/chemokine arrays were evaluated. Incidence of AAA rupture was evaluated in the remaining surviving rats until POD14 (Figure 1A). Results: Compared with controls, the incidence of AAA rupture was reduced in treated male AAA rats (0% vs 56%, p <0.001; and tended to decreased in treated female AAA rats (18% vs 42%, p =0.09;). PET/CT demonstrated that male and female treatment groups had significantly decreased 64 Cu-DOTA-ECL1i uptake in AAAs ( p= 0.02 for male AAAs , p <0.001 for females, Figure 1B). All cytokines, including MCP-1, RANTES, IL-17A, IL-18, IL-1B, IL-6, IL-10, except TNF-a were significantly reduced in the male treatment group compared to control group ( p <0.05; Figure 1C). Interestingly, in the female treatment group, IL-1B was significantly decreased ( p <0.05), and RANTES was significantly increased ( p <0.05). Conclusion: In rats, CCR2 appears to be a promising theranostic biomarker for AAAs. CCR2i can greatly impact AAA tissue inflammation and reduces the incidence of AAA rupture. Differences between male and female rats suggest that CCR2 signaling may be different in AAA between sexes and highlights future avenues of further investigation.
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