Ornithine Decarboxylase 1 Mediated Putrescine Metabolism Promotes Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a localized permanent enlargement of the aorta. With the aging population, the incidence of AAA rupture is increasing significantly. This leads to an extremely high mortality rate. However, the pathogenesis of AAA remains poorly understood, and there are currently no effective drugs available to inhibit its growth and prevent rupture. Our research revealed that ornithine decarboxylase (ODC1) expression is significantly elevated in aneurysm tissues from both AAA patients and mouse AAA models. Immunofluorescence co-localization studies demonstrated that ODC1 is expressed in macrophages and vascular smooth muscle cells (VSMCs) which are closely associated with AAA development. We induced AAA in mice using both PPE and angiotensin II methods, administering putrescine, a metabolite of ODC1, and DFMO, an ODC1 inhibitor, in their drinking water. We found that putrescine promotes the progression of AAA, while DFMO effectively inhibits it. In addition, in vitro experiments showed that putrescine enhances NF-κB pathway activation and release of pro-inflammatory factors such as TNF-α and IL-6 in mouse macrophages. Conversely, DFMO inhibits LPS-induced NF-κB pathway activation and release of these proinflammatory factors in mouse macrophages. Furthermore, putrescine promotes the release of MMP2 and MMP9 in VSMCs, leading to a loss of contractile function, whereas DFMO inhibits AngII-induced release of MMP2 and MMP9 and preserves contractile characteristics in (VSMCs). Overall, these data point to ODC1 as a potential therapeutic target for AAA treatment, and that DFMO holds promise as a therapeutic agent for managing this condition.