title: Celiprolol activates eNOS through the PI3K-Akt pathway and inhibits VCAM-1 Via NF-kappaB induced by oxidative stress.
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 beta1-antagonist with weak beta2-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-kappaB (NF-kappaB), 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-kappaB 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-kappaB, 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-beta1 gene expression. In conclusion, celiprolol suppresses VCAM-1 expression because of inhibition of oxidative stress, NF-kappaB, and signal transduction, while increasing eNOS via stimulation of the PI3K-Akt signaling pathway and improving cardiovascular remodeling.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. nao-koba@dokkyomed.ac.jp
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Mita
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takeaki
authors.initials: T
authors.lastname: Honda
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hara
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Nakano
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tsubokou
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017272:Celiprolol / Q000494:pharmacology*; D003331:Coronary Vessels / Q000473:pathology; D003900:Desoxycorticosterone; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011433:Propranolol / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D012965:Sodium Chloride; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D017272:Celiprolol; D003900:Desoxycorticosterone; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D016328:NF-kappa B; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D011433:Propranolol; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012965:Sodium Chloride; D019010:Vascular Cell Adhesion Molecule-1; C496316:Nos3 protein, rat; C494920:Akt1 protein, rat