Viswambharan Hema, Carvas João M, Antic Vladan, Marecic Ana, Jud Corinne, Zaugg Christian E, Ming Xiu-Fen, Montani Jean-Pierre, Albrecht Urs, Yang Zhihong
Department of Medicine, Division of Physiology, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland.
Circulation. 2007 Apr 24;115(16):2188-95. doi: 10.1161/CIRCULATIONAHA.106.653303. Epub 2007 Apr 2.
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.
Compared with the wild-type littermates, mice with Per2 mutation exhibited impaired endothelium-dependent 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-M3 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.
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.
生物钟调节包括心血管功能和新陈代谢在内的生物过程。在本研究中，我们在小鼠模型中研究了生物钟基因Period2（Per2）在内皮功能中的作用。
与野生型同窝小鼠相比，Per2基因敲除小鼠的主动脉环对乙酰胆碱的内皮依赖性舒张功能受损。在从非活动期到活动期的转变过程中，野生型小鼠的这种反应进一步增强，而Per基因敲除小鼠的这种反应则进一步减弱。在离子霉素刺激下，Per2基因敲除小鼠也出现了内皮功能障碍，而环氧化酶抑制剂吲哚美辛可改善这一情况。在Per2基因敲除小鼠的主动脉中，内皮乙酰胆碱-M3受体或内皮型一氧化氮合酶蛋白的表达没有变化，但环氧化酶-1（而非环氧化酶-2）的蛋白水平升高。与Per2基因敲除小鼠相比，野生型小鼠对ATP的内皮依赖性舒张反应更强，而吲哚美辛可减弱这种反应。在静息的主动脉环中，ATP在Per2基因敲除小鼠中引起的内皮依赖性收缩比野生型小鼠更强，而吲哚美辛可消除这种收缩。Per2基因敲除小鼠的内皮功能障碍与高血压或血脂异常无关。
小鼠Per2基因突变与主动脉内皮功能障碍有关，包括一氧化氮和血管舒张性前列腺素生成减少以及环氧化酶-1衍生的血管收缩物质释放增加。结果表明Per2基因在维持正常心血管功能中起重要作用。
