Whole body C‐cbl Associated Protein (CAP) deleted mice display impaired endothelium dependent dilation and nitric oxide bioavailability

Abstract

In endothelial cells, high glucose impairs insulin‐stimulated endothelial nitric oxide synthase (eNOS) activity in a c‐casitas B lymphoma (c‐cbl) associated protein (CAP)‐dependent manner. In adipocytes, the CAP/cbl complex associates with lipid rafts and participates in GLUT4 trafficking upon insulin stimulation. Together, these findings raise the possibility that CAP/cbl participate in eNOS activation/trafficking. We tested the hypothesis that compared to wild‐type (CAP+/+) littermates, arterial function is impaired in mice with whole body CAP deletion (CAP−/−). Maximal ex vivo carotid artery endothelium dependent dilation (EDD) to acetylcholine (ACh) was reduced in CAP−/− versus CAP+/+ (72.2 ± 7.3 v 99.84 ± 0.8%, p < 0.05). Impaired EDD was associated with reduced nitric oxide (NO), evidenced by the abolition of differences in EDD after incubation with a NOS inhibitor. This does not appear to be associated with increased superoxide, as incubation with a superoxide dismutase mimetic failed to improve dilation in CAP−/− mice. Endothelium independent dilation was not different between groups. CAP deletion was without effect on aortic stiffness (pulse wave velocity) or mean arterial pressure (p's > 0.19). CAP deletion results in impaired EDD via a superoxide‐independent reduction in NO. Although the mechanism is unknown, dysregulation of eNOS trafficking is a possibility requiring examination.