Colchicine Does Not Reduce Abdominal Aortic Aneurysm Growth in a Mouse Model

Abstract

Background and Aims. The nacht domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is upregulated in human abdominal aortic aneurysm (AAA), but its pathogenic role is unclear. The aims of this study were firstly to examine whether the inflammasome was upregulated in a mouse model of AAA and secondly to test whether the inflammasome inhibitor colchicine limited AAA growth. Methods. AAA was induced in eight-week-old male C57BL6/J mice with topical application of elastase to the infrarenal aorta and oral 3-aminopropionitrile (E-BAPN). For aim one, inflammasome activation, abdominal aortic diameter, and rupture were compared between mice with AAA and sham controls. For aim two, 3 weeks after AAA induction, mice were randomly allocated to receive colchicine ( n = 28 , 0.2 mg/kg/d) or vehicle control ( n = 29 ). The primary outcome was the rate of maximum aortic diameter increase measured by ultrasound over 13 weeks. Results. There was upregulation of NLRP3 markers interleukin- (IL-) 1β (median, IQR; 15.67, 7.11-22.60 pg/mg protein versus 6.87, 4.54-11.60 pg/mg protein, p = .048 ) and caspase-1 (109, 83-155 relative luminosity units (RLU) versus 45, 38-65 RLU, p < .001 ) in AAA samples compared to controls. Aortic diameter increase over 80 days (mean difference, MD, 4.3 mm, 95% CI 3.3, 5.3, p < .001 ) was significantly greater in mice in which aneurysms were induced compared to sham controls. Colchicine did not significantly limit aortic diameter increase over 80 days (MD -0.1 mm, 95% CI -1.1, 0.86, p = .922 ). Conclusions. The inflammasome was activated in this mouse model of AAA; however, daily oral administration of colchicine did not limit AAA growth.

Colchicine protects against the development of experimental abdominal aortic aneurysm

“…In 2022, James et al reported that colchicine could not limit the growth of already established AAA [ 20 ]. James’ work and ours were both designed to investigate the impact of colchicine on AAA formation but focused on different stages.…”

“…In 2022, James et al reported that colchicine did not reduce AAA growth in a mice model with administration of colchicine (0.2 mg/kg/d via gavage) beginning from day 21 after the induction of AAA for a subsequently consecutive 69 days with the purpose to explore the therapeutic effects of colchicine on an established AAA mice model [ 20 ]. Given the facts that AAA is life threatening and associated with vascular walls’ inflammation, and colchicine could prevent neutrophils migration and interleukin-1β activation, we hypothesized that colchicine could protect against the development of AAA at the early stage.…”

Pathogenesis and management of abdominal aortic aneurysm

“… 147 In contrast, a new model that combines two methods of inducing AAA using application of elastase to the adventitia of the infra-renal aorta and oral administration of a lysyl oxidase inhibitor holds more promise for testing drugs. 148 In this model, expansion of aortic diameter occurs over 3 months ( Figure 7 ). The model also illustrates typical human AAA characteristics of true aneurysm formation, intra-luminal thrombus, marked aortic wall inflammation, and a rupture rate of ∼30%.…”

“…The model also illustrates typical human AAA characteristics of true aneurysm formation, intra-luminal thrombus, marked aortic wall inflammation, and a rupture rate of ∼30%. 148 The use of this and other novel animal models along with rigorous study design similar to clinical trials may identify drugs more likely to translate to patients.…”

Potential application of peripheral blood biomarkers in intracranial aneurysms

“…Zhao et al ( 81 ) conducted an animal study that demonstrated the protective effect of colchicine against the development of experimental abdominal aortic aneurysms. However, Phie et al ( 82 ) suggested that colchicine lacked efficacy in reducing the growth of abdominal aortic aneurysms in a mouse model. Although these findings primarily pertained to abdominal aortic aneurysms, they inspired intriguing possibilities regarding the potential applications of colchicine in managing IAs.…”