Mutation of the Circadian Clock Gene Per2 Alters Vascular Endothelial Function

Abstract

Background-The circadian clock regulates biological processes including cardiovascular function and metabolism. In the present study, we investigated the role of the circadian clock gene Period2 (Per2) in endothelial function in a mouse model. Methods and Results-Compared with the wild-type littermates, mice with Per2 mutation exhibited impaired endotheliumdependent relaxations to acetylcholine in aortic rings suspended in organ chambers. During transition from the inactive to active phase, this response was further increased in the wild-type mice but further decreased in the Per2 mutants. The endothelial dysfunction in the Per2 mutants was also observed with ionomycin, which was improved by the cyclooxygenase inhibitor indomethacin. No changes in the expression of endothelial acetylcholine-M 3 receptor or endothelial nitric oxide synthase protein but increased cyclooxygenase-1 (not cyclooxygenase-2) protein levels were observed in the aortas of the Per2 mutants. Compared with Per2 mutants, a greater endothelium-dependent relaxation to ATP was observed in the wild-type mice, which was reduced by indomethacin. In quiescent aortic rings, ATP caused greater endothelium-dependent contractions in the Per2 mutants than in the wild-type mice, contractions that were abolished by indomethacin. The endothelial dysfunction in the Per2 mutant mice is not associated with hypertension or dyslipidemia. Conclusions-Mutation in the Per2 gene in mice is associated with aortic endothelial dysfunction involving decreased production of NO and vasodilatory prostaglandin(s) and increased release of cyclooxygenase-1-derived vasoconstrictor(s). The results suggest an important role of the Per2 gene in maintenance of normal cardiovascular functions.

Genetic diversity patterns at the human clock gene period 2 are suggestive of population-specific positive selection

“…Mutations in this gene have been associated with a wide spectrum of phenotypes that include not only clock-related disorders, such as those associated with the sleep -wake cycle, 4 but also other diseases such as tumors, 8 -10 cardiovascular dysfunctions 11 and enhanced alcohol intake. 12 In this study, we analyze the extent of diversity at the PER2 gene in a worldwide human sample.…”

Circadian clock and vascular disease

“…Global Per2 mutant mice also show lower BP. 24 In contrast, the endothelial-specific deletion of Bmal1 did not affect the variation in BP, suggesting that the peripheral clock in endothelial cells does not solely induce diurnal BP rhythm. 41 A genetic association study showed that a single-nucleotide polymorphism within the bmal1 promoter is associated with hypertension and type II diabetes, 42 providing support that the molecular clock is involved in the pathogenesis of metabolic disorders.…”

“…Mice with the Per2 mutation produced lesser amounts of nitric oxide and vasodilatory prostaglandins and more cyclooxygenase-1-derived vasoconstrictors than the wild type, resulting in impaired endothelium-dependent relaxation in response to acetylcholine. 24 Endothelial dysfunction was also observed in mice with Bmal1 knockout and CLOCK mut . 25 Akt signaling and nitric oxide production were reduced in Bmal1 knockout arteries, and these arteries became more susceptible to thrombosis formation.…”

Per3 VNTR polymorphism and chronic heart failure

“…Recently correlation between VNTR Per3 polymorphism and the extreme diurnal preference (the 5/5 allele associated with morningness and the 4/4 allele with eveningness) has been found 18 . On the other hand, a certain mutation in Per2 gene, which has a similar function in the clock machinery to Per3, has been associated with impaired vascular endothelial function in mice and with familial sleeping disorders in humans 27 . The connection between both could be viewed from the perspective of the possible effect of sleep deprivation on cardiac autonomic control, associating homozygozity in Per3 VNTR with heart rate (HR) and heart rate variability (HRV) (ref.…”