Background and aims:

Currently, no pharmacological therapy has been validated by randomized controlled trials to limit abdominal aortic aneurysm (AAA) progression or rupture. As response to vascular stress, local release of danger associated molecular patterns (DAMPs) has been shown to be a main contributor to adverse remodeling of the aortic wall. One of these DAMPs is Cyclophilin A (CyPA), that physiologically fulfills intracellular functions but acts as a pathological effector for aneurysm formation when being secreted into the local microenvironment.

In this study we aimed to demonstrate the pathological role of secreted CyPA on the induction of AAAs and developed a novel pharmacological intervention strategy to inhibit formation and progression of AAAs.

Methods:
We used a robust animal model that is characterized by hypertension, hyperlipidemia and reactive oxygen species. To this effect, ApoE-/- mice were infused continuously with Angiotensin II (Ang II) or NaCl (control) by an osmotic minipump for 28 days (n=39). Additionally, we supplied the pumps with a self-developed neutralizing antibody, which is specifically directed against extracellular CyPA, or an idiotypic IgG control. To monitor the development of aortic aneurysms, we performed ultrasound on the abdominal aorta every seven days, including vascular strain analyses and three-dimensional reconstruction of AAA or normal aortas. In a second step we performed in silico analyses on hemodynamic characteristics at the side of AAAs.

Results:
After 28 days of treatment, we observed a significant increase in aortic diameter in the control group of Ang II-treated mice, whereas treatment with Ang II plus anti-CyPA significantly attenuated development of AAAs (p<0.0001). Our findings were supported by an increased survival from aortic dissection or rupture, less inflammation, fibrosis and matrix remodeling (p=0.001) of the aortic wall in the group of Ang II and our antibody.

Conclusion:
Our results demonstrate that the selective inhibition of extracellular CyPA reduces the development of AAAs and may provide a novel strategy to prevent or slow down the formation of AAA.