Exendin‑4 reverses endothelial dysfunction in mice fed a high‑cholesterol diet by a GTP cyclohydrolase‑1/tetrahydrobiopterin pathway

The present study examined whether exendin‑4 (Ex4) can improve the endothelial dysfunction of apolipoprotein E knockout (APOE‑KO) mice fed a high‑cholesterol diet and the potential mechanism by which it acts. Genetically wild‑type (WT) C57BL/6 mice and APOE‑KO mice of C57BL/6 background, were each randomly assigned to receive either Ex4 treatment (Ex4‑treated, for 8 weeks) or not (control). The 4 groups were fed the same high‑cholesterol diet for 8 weeks. The following were measured at the end of the eighth week: Endothelium‑dependent vasodilation of the arteries; plasma nitric oxide (NO) and metabolic index; levels of endothelial NO synthase (eNOS); phosphorylated eNOS (p‑eNOS; Ser‑1,177); guanosine triphosphate cyclohydrolase‑1 (GCH1); and tetrahydrobiopterin (THB). Ex4 treatment was associated with higher p‑eNOS levels in the WT group and in the APOE‑KO group, and higher vascular expression of GCH1 and higher arterial THB content, compared with baseline values. The results of the present study suggested that Ex4 may exert cardioprotective effects by reversing high‑cholesterol diet‑induced endothelial dysfunction in APOE‑KO mice. The protective mechanism is probably associated with the promotion of the expression levels of GCH1 protein and THB that maintain the normal function of eNOS.