Regulation of circadian rhythmicity by endothelial SIRT1

Abstract

Circadian rhythm is a physiological phenomenon that is defined by an endogenous and enduring, 24-hour cycle driven by diurnal variation. All creatures, including animals, plants, fungi, etc., have circadian rhythms. The circadian oscillator, which oscillates with a period of around 24 hours to synchronize the physiological characteristics of the organism with the circadian rhythm, is what drives the circadian rhythm. This feedback loop is created by the impact of gene products on gene promoters. Mammals have several core clock driver genes, including cryptochrome circadian regulator 1 (CRY1), nuclear receptor subfamily 1 group D member 1 (REV-ERBα), period circadian regulator 2 (PER2), and brain and muscle Arnt-like protein-1 (BMAL1). The circadian rhythm has a direct impact on several metabolic, cardiovascular, and other associated disorders. Disruption of circadian rhythms can cause a wide variety of cardio metabolic diseases. SIRT1 (sirtuin 1) is regarded as a lifespan regulator and energy sensor. It is a NAD+-dependent deacetylase that, through its deacetylase activity, takes part in several physiological metabolic processes. SIRT1 has been found to have an anti-aging and protective cardiovascular function. The goal of the current work was to examine the protective role of endothelium SIRT1 against disruption and dysfunction of the cardiovascular and metabolic circadian rhythms caused by PER2 mutation. At 10 weeks of age, radio telemetry implants were placed in wild-type mice (WT) on the C57BL/6 background, endothelial SIRT1 overexpression mice (EC-SIRT1), PER2 mutant mice (PER2MUT), and endothelial SIRT1 overexpressing in PER2MUT mice (PER2MUT/EC-SIRT1). At 20 weeks of age, real-time blood pressure, heart rate, and body temperature were monitored. The findings demonstrated that endothelial SIRT1 can reverse cardiovascular abnormalities induced by PER2 mutation, including hypertension and disruptions of the cardiovascular circadian rhythm. Severe metabolic dysfunctions and disturbances of the metabolic circadian rhythm can be induced by PER2 mutation. In order to characterize the role of brown adipose tissue (BAT), an essential organ for thermogenesis and metabolism. BAT from 20-week-old PER2MUT and EC-SIRT1 mice were transplanted into four-week-old PER2MUT mice, and recipient mice were implanted with radio telemetry implants at 10 weeks of age. At 20 weeks of age, blood pressure, heart rate, and body temperature were then continuously monitored. The outcomes demonstrated that BAT of EC-SIRT1 mice could lower blood pressure and body temperature, restore cardiovascular circadian rhythm and body temperature circadian rhythm, and BAT may be a crucial organ to regulate cardiovascular abnormalities and circadian rhythm disorders brought on by PER2 mutation. In conclusion, the present study showed that overexpression of endothelial SIRT1 restored the cardiovascular and metabolic circadian rhythm disturbances induced by PER2 mutation, and prevented hypertension, metabolic abnormalities in PER2 mutant mice.