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(Hypertension. 2003;42:1004.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Celiprolol Activates eNOS Through the PI3K-Akt Pathway and Inhibits VCAM-1 Via NF-B Induced by Oxidative Stress

Naohiko Kobayashi; Shin-ichiro Mita; Kohtaro Yoshida; Takeaki Honda; Tsutomu Kobayashi; Kazuyoshi Hara; Shigefumi Nakano; Yusuke Tsubokou; Hiroaki Matsuoka

From the Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Japan.

Correspondence to Naohiko Kobayashi, MD, PhD, FAHA, Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. E-mail nao-koba{at}dokkyomed.ac.jp

Vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species play critical roles in early atherogenesis, and nitric oxide (NO) is an important regulator of the cardiovascular system. Although celiprolol, a specific ß₁-antagonist with weak ß₂-agonistic action, stimulates endothelial nitric oxide synthase (eNOS) production, the mechanisms remain to be determined. Because it was recently reported that phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt are implicated in the activation of eNOS and that regulation of VCAM-1 expression is mediated via nuclear factor-B (NF-B), we hypothesized that celiprolol activates phosphorylation of eNOS through the PI3K-Akt signaling pathway; that celiprolol modulates VCAM-1 expression, which is associated with inhibiting NF-B phosphorylation; and that celiprolol suppresses NAD(P)H oxidase p22phox, p47phox, gp91phox, and nox1 expression in the left ventricle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. eNOS and Akt phosphorylation upregulated by celiprolol alone were suppressed by treatment with celiprolol plus wortmannin. Increased expression of VCAM-1, p22phox, p47phox, gp91phox, nox1, activated p65 NF-B, c-Src, p44/p42 extracellular signal-regulated kinases, and their downstream effector p90 ribosomal S6 kinase phosphorylation in DOCA rats was inhibited by celiprolol. Celiprolol administration resulted in a significant improvement in cardiovascular remodeling and suppression of transforming growth factor-ß1 gene expression. In conclusion, celiprolol suppresses VCAM-1 expression because of inhibition of oxidative stress, NF-B, and signal transduction, while increasing eNOS via stimulation of the PI3K-Akt signaling pathway and improving cardiovascular remodeling.

Key Words: receptors, adrenergic, ß • adrenergic receptor blockers • kinase • nitric oxide • oxidative stress • cell adhesion molecules

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