Dihydroorotate Dehydrogenase Inhibition by Teriflunomide Alleviates Endothelial Dysfunction of Arterial Grafts in Rats

Background: Ischemia/reperfusion (IR) injury affects endothelial cells by disrupting their normal barrier function, vascular tone, and expression of adhesion molecules. Inhibition of dihydroorotate dehydrogenase with teriflunomide (TERI) has been shown to reduce inflammation and oxidative stress damage. We hypothesize that TERI alleviates endothelial dysfunction in an experimental bypass model.

Methods: Rats (n = 8/group) were divided into three groups. Aortic arches from control rats were harvested, and aortic rings were prepared and mounted in organ baths. Aortic rings from the IR and IR-TERI groups were stored for 1 hour in saline-supplemented DMSO vehicle or TERI (5 µM), respectively, before implantation into the recipients’ abdominal aorta. After 1 hour of in vivo blood reperfusion, aortic rings were studied ex vivo for endothelium-dependent vasorelaxation to acetylcholine. Immunohistochemical analysis was performed to detect intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, platelet endothelial cell adhesion molecule (PECAM)-1/CD31, and DNA fragmentation (using a TUNEL assay) was conducted.

Results: The impaired maximum relaxation to acetylcholine in the IR group, compared with controls, was ameliorated by TERI (control 91 ± 2%, IR 27 ± 2%, IR-TERI 52 ± 2%, p < 0.05). TERI also prevented the upregulation of ICAM-1 (score: control 0.2 ± 0.1, IR-Placebo 1.1 ± 0.2, IR-TERI 0.2 ± 0.1, p < 0.001) and VCAM-1 (score: control 0.8 ± 0.1, IR-Placebo 9.3 ± 0.6, IR-TERI 2.9 ± 0.4, p < 0.001) in the IR group compared with controls. Furthermore, TERI increased the decreased endothelial PECAM-1 expression in the IR group compared with controls (score: control 10.2 ± 0.5, IR-Placebo 4.5 ± 0.6, IR-TERI 6.7 ± 0.7, p < 0.001). Additionally, the elevated percentage of TUNEL-positive cells, indicating DNA fragmentation in the intima and media of the aortic wall rings in the IR group compared with controls, was reduced by TERI (control 37 ± 3%, IR-Placebo 49 ± 2%, IR-TERI 22 ± 2%, p < 0.05).

Conclusion: TERI mitigates endothelial dysfunction in a rat arterial revascularization model by reducing inflammatory responses and apoptotic DNA fragmentation.

Publikationsverlauf

Artikel online veröffentlicht:
11. Februar 2025