Srt1720 alleviates endothelial crif1 deficiency-induced cardiac function

Objective: CR6-interacting factor1 (CRIF1) is a mitochondrial inner membrane and plays an important role in peptide synthesis and oxidative phosphorylation. Cardiomyocyte-specific deletion of CRIF1 led to an exaggerated decline in cardiac function and impaired cardiomyopathy. However, whether endothelial deletion of CRIF1 influences cardiac function has not yet been fully determined. Design and method: We developed an endothelial cell-specific CRIF1 deletion mouse and observed cardiac function in vivo. Results: Our results showed that endothelial deletion of CRIF1 increased heart-to-body weight ratio, enhanced lethality, and lowered fractional shortening of the left ventricle, which contributed to severe cardiac dysfunction. Furthermore, we observed severe mitochondrial dysfunction, decreased ATP level, inflammation, and enhanced oxidative stress in CRIF1 KO mice heart tissues, along with reduced SIRT1 expression. The SIRT1 activator SRT1720 attenuated cardiac dysfunction by activating endothelial nitric oxide synthase, reducing oxidative stress, inhibiting inflammation, and endothelial junction associated protein Zonula occludens-1 in CRIF1 KO mice. Conclusions: Therefore, our results suggest that endothelial mitochondrial OXPHOS dysfunction plays an essential role in maintaining cardiac function, and SIRT1 activator could be a promising therapeutic strategy for endothelial dysfunction-induced cardiac dysfunction.