Betaxolol stimulates eNOS production associated with LOX-1 and VEGF in Dahl salt-sensitive rats.
OBJECTIVE
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and vascular endothelial growth factor (VEGF) may play key roles in atherosclerosis, and have been shown to regulate nitric oxide (NO) production. However, the molecular mechanisms by which betaxolol, a specific beta 1-antagonist, stimulates endothelial NO synthase (eNOS) expression associated with LOX-1 and VEGF are unclear. We hypothesized that in the left ventricle of Dahl salt-sensitive (DS) rats, betaxolol reduces production of LOX-1 by suppressing NAD(P)H oxidase p47phox expression; betaxolol stimulates eNOS production associated with expression of VEGF and LOX-1; and betaxolol inhibits adhesion molecule and signal transduction, which may be involved in cardiovascular remodeling.


METHODS
After 5 weeks of feeding an 8% NaCl diet to 6-week-old DS rats (i.e. at 11 weeks of age), a distinct stage of concentric left ventricular hypertrophy was noted. Betaxolol (0.9 mg/kg per day) was administered to 6-week-old DS rats for 5 weeks until the onset of left ventricular hypertrophy stage.


RESULTS
Decreased expression of eNOS and VEGF in DS rats was increased by betaxolol. Upregulated LOX-1, NAD(P)H oxidase p47phox, intercellular and vascular cell adhesion molecule-1 expression and phosphorylations of p38 mitogen-activated protein kinase and p65 nuclear factor-kappa B activity were inhibited by betaxolol. Betaxolol administration resulted in significant improvement of cardiovascular remodeling and suppression of transforming growth factor-beta 1 and type I collagen expression.


CONCLUSIONS
These results suggest that cardioprotective effects of betaxolol may stimulate eNOS production associated with VEGF and LOX-1, and inhibit adhesion molecule and signal transduction in DS rats.
Kobayashi
Naohiko
N
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, 321-0293, Japan. nao-koba@dokkyomed.ac.jp
Yoshida
Kohtaro
K
Mita
Shin-ichiro
S
Honda
Takeaki
T
Hara
Kazuyoshi
K
Nakano
Shigefumi
S
Tsubokou
Yusuke
Y
Matsuoka
Hiroaki
H
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D015784:Betaxolol / Q000494:pharmacology*; D024042:Collagen Type I / Q000235:genetics; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008297:Male; D019255:NADPH Oxidases; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation; D051381:Rats; D020303:Rats, Inbred Dahl; D011973:Receptors, LDL / Q000235:genetics*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000959:Antihypertensive Agents; D024042:Collagen Type I; D016328:NF-kappa B; C495136:OLR1 protein, rat; D010750:Phosphoproteins; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; C508962:Tgfb1 protein, rat; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D048051:p38 Mitogen-Activated Protein Kinases; D015784:Betaxolol