Overexpression of SIRT1 in vascular endothelial cells prevents premature vascular and metabolic ageing in Per2 mutant mice

Abstract

Background- SIRT1 is a longevity regulator implicated in the regulation of circadian rhythmicity, which facilitates the organisms to adapt to the external environment. PER2 is a member of the Period family of circadian regulators participating in the transcription-translational feedback loop of clock-control mechanisms. The present study was designed to evaluate the protective effects of SIRT1 in vascular endothelial cells on Per2 mutation-induced vascular and metabolic abnormalities. Methods and Results-Wild type (WT) and PER2 mutant (Per2Brdm2) mice without or with human SIRT1 selectively overexpressed in vascular endothelial cells (Per2Brdm2EC-SIRT1) were used in the present study. Mice were housed under 12-hour light/dark cycle and a controlled temperature conditions with free access to water and chow. Radiotelemetry transmitters were implanted for monitoring arterial blood pressures. Compared to WT mice, Per2Brdm2 mice exhibited a loss of dipping in the diurnal blood pressures at the age of eight-weeks and hypertension at the age of 24-weeks, both of which were prevented by SIRT1 overexpression in endothelial cells. The premature metabolic ageing phenotype caused by Per2 mutation, including decreased skeletal muscle mass and increased fat mass as well as altered insulin sensitivity, was also prevented by endothelial overexpression of SIRT1. Preliminary metabolomics analyses indicated that endothelial SIRT1 elicits the anti-vascular and metabolic ageing activities via modulating amino acid metabolism in skeletal muscle. Conclusion-Endothelial SIRT1 represents a promising target for anti-ageing therapies in both vascular and metabolic diseases.