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(Circulation Research. 2008;102:607.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Reduced Nitric Oxide Causes Age-Associated Impairment of Circadian Rhythmicity

Takeshige Kunieda^*, Tohru Minamino^*, Kentaro Miura, Taro Katsuno, Kaoru Tateno, Hideyuki Miyauchi, Shuichi Kaneko, Christopher A. Bradfield, Garret A. FitzGerald, Issei Komuro

From the Department of Cardiovascular Science and Medicine (T. Kunieda, T.M., K.M., T. Katsuno, K.T., H.M., I.K.), Chiba University Graduate School of Medicine, Japan; Institute for Translational Medicine and Therapeutics (T. Kunieda, G.A.F.), University of Pennsylvania, Philadelphia; PRESTO (T.M.), Japan Science and Technology Agency, Saitama, Japan; Department of Disease Control of Homeostasis (S.K.), Kanazawa University Graduate School of Medicine, Ishikawa, Japan; and McArdle Laboratory for Cancer Research (C.A.B.), Madison, Wis.

Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp

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.

Key Words: aging • clock gene • endothelial nitric oxide synthase