Abstract 3000: Mir-146a Deficiency Differentially Regulates Sexual Dimorphism Of Abdominal Aortic Aneurysms In Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 44; no. Suppl_1
• Main Authors: Ramesh, Nithya, Javidan, Aida, Downey, Eddie, Subramanian, Venkateswaran
• Format: Journal Article
• Language: English
• Published: 01.05.2024
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.44.suppl_1.3000

Abstract only Background and Objective: Abdominal aortic aneurysms (AAAs) are permanent aortic dilations with 80% mortality after rupture. AAA exhibits sexual dimorphism, with males at higher risk in both mice and humans. In spite of lower incidence, women acquire aggressive aneurysm growth and rupture at smaller sizes, compared to men. Despite this oddity, mechanisms driving the sexual dimorphism of AAA have not been defined. Previously, we demonstrated that Lysyl Oxidase (LOX) inhibition abolishes sexual dimorphism of AAA in mice. Recent clinical studies showed elevated miR-146a levels, an anti-inflammatory miRNA, in plasma and AAA tissues from patients. In our preliminary studies, we found that aortic miR-146a is significantly lower in females compared to male mice. However, the contribution of miR-146a in the sexual dimorphism of AAAs is unknown. In this study, we examined the role of miR-146a in AAA sexual dimorphism in mice by administering β-aminopropionitrile (BAPN), a LOX inhibitor and Angiotensin II (AngII) concurrently. Methods and Results: 8 -10 week old male and female C57BL/6J mice that were either miR146a wild type (WT) or deficient (KO; n=18-24/per group) were infused with saline or Ang II (1,000 ng/kg/min) via subcutaneous osmotic mini-pump for 28 days. In addition, mice were co-administered with BAPN (1 mg/ml; 0.15g/kg/d in drinking water) from day 0-14. miR-146a deficiency had no effect on body weight and blood pressure in both male and female mice. AngII+BAPN-administration increased AAA in both male (82%;19/23) and female (72%;18/25) mice compared to saline+BAPN controls. Interestingly, miR-146a deficiency profoundly but significantly increased AAA in males (WT=1.5 ± 0.1 versus KO=2.3 ± 0.1 mm, P<0.05), but significantly decreased AAA in females (WT=1.5 ± 0.1 versus KO=1.2 ± 0.1 mm, P<0.05). By RNA sequencing and qPCR, we identified several differentially expressed genes in the absence of miR-146a, with RFLNA upregulated and ELAVL2 downregulated in male KO mice, and SLC38A5, CCND2, DUSP10 genes upregulated in female KO mice. Ongoing studies aim to delineate the role of these genes in miR-146a-mediated sexual dimorphism of AAA. Conclusion: These findings demonstrate that miR-146a plays a critical role in mediating sexual dimorphism of AAA in mice.