Published Online
on October 13, 2003

A more recent version of this article appeared on November 1, 2003

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Submitted on November 20, 2002
Revised on December 19, 2002

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; and Hiroaki Matsuoka

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

^* To whom correspondence should be addressed. E-mail: nao-koba{at}dokkyomed.ac.jp.

Abstract--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 ₁-antagonist with weak ₂-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-1 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, • adrenergic receptor blockers • kinase • nitric oxide • oxidative stress • cell adhesion molecules

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