Reduced nitric oxide causes age-associated impairment of circadian rhythmicity.
Impairment of circadian rhythmicity in the elderly has been suggested to cause age-associated diseases such as atherosclerosis and hypertension. Endothelium-derived nitric oxide (NO) is a critical regulator of cardiovascular homeostasis, but its production declines with aging, thereby inducing vascular dysfunction. We show here that impaired circadian rhythmicity is related to a decrease of NO production with aging. Treatment with an NO donor significantly upregulated the promoter activity of the clock gene Period via the cAMP response element-dependent and the E-box enhancer element-dependent pathways. Both phosphorylation and S-nitrosylation by NO are involved in this upregulation. In aged animals, endothelial NO synthase activity was markedly decreased during the daytime, along with impairment of clock gene expression and the circadian variation in blood pressure. Treatment of aged animals with an NO donor significantly improved the impairments. Inhibition of NO synthase activity also led to impairment of clock gene expression and blood pressure rhythm. These results suggest that NO is a key regulator of the circadian clock in the cardiovascular system and may be a novel target for the treatment of age-associated alteration of circadian rhythms.
Kunieda
Takeshige
T
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Minamino
Tohru
T
Miura
Kentaro
K
Katsuno
Taro
T
Tateno
Kaoru
K
Miyauchi
Hideyuki
H
Kaneko
Shuichi
S
Bradfield
Christopher A
CA
FitzGerald
Garret A
GA
Komuro
Issei
I
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D021081:Chronobiology Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000627:therapeutic use; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009687:Nuclear Proteins; C539022:PER1 protein, human; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester