To determine whether mitochondrial dysfunction in endothelial cells play a key role in vascular disease, we examined the phenotype of endothelial-specific CR6-interacting factor 1 (CRIF1) knockout (CRIF1 KO) mice and in vitro pathophysiological mechanisms.Design and Method:
CRIF1 KO mice exhibited lower body weight and cardiac hypertrophy. Downregulation of CRIF1 in vascular endothelial cells caused disturbances in the mitochondrial OXPHOS (oxidative phosphorylation) complexes, mitochondrial morphology, and function leading to enhanced mitochondrial reactive oxygen species (ROS) production and higher mitochondrial membrane potential (MMP).Results:
Downregulation of CRIF1 also caused decreased Sirt1 expression along with increased endothelial nitric oxide synthase (eNOS) acetylation leading to reduced nitric oxide (NO) production. Similar results were obtained in mice with CRIF1-deficient vascular endothelial cells. Endothelium-dependent vasorelaxation (EDR) of aortic rings from CRIF1 KO mouse was considerably less than in wild-type mice. Notably, EDR was partially recovered following in adSirt1 treated aortic rings from CRIF1 KO mice.Conclusions:
Taken together, these findings indicate that CRIF1 plays an important role in the maintaining mitochondrial and endothelial function through its effects on the SIRT1-eNOS pathway.