Betaxolol stimulates eNOS production associated with LOX-1 and VEGF in Dahl salt-sensitive rats.

Abstract

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.

• Authors: Naohiko Kobayashi, Kohtaro Yoshida, Shin-ichiro Mita, Takeaki Honda, Kazuyoshi Hara, Shigefumi Nakano, Yusuke Tsubokou, Hiroaki Matsuoka
• Journal: Journal of hypertension (J Hypertens) Vol. 22 Issue 7 Pg. 1397-402 (Jul 2004) ISSN: 0263-6352 [Print] Netherlands
• PMID: 15201557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Collagen Type I
• NF-kappa B
• OLR1 protein, rat
• Phosphoproteins
• Receptors, LDL
• Receptors, Oxidized LDL
• Scavenger Receptors, Class E
• Tgfb1 protein, rat
• Transcription Factor RelA
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Vascular Cell Adhesion Molecule-1
• Vascular Endothelial Growth Factor A
• Intercellular Adhesion Molecule-1
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type III
• Nos3 protein, rat
• NADPH Oxidases
• neutrophil cytosolic factor 1
• p38 Mitogen-Activated Protein Kinases
• Betaxolol

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Betaxolol (pharmacology)
• Collagen Type I (genetics)
• Hypertension (drug therapy, pathology, physiopathology)
• Intercellular Adhesion Molecule-1 (genetics)
• Male
• NADPH Oxidases
• NF-kappa B (genetics, metabolism)
• Nitric Oxide Synthase (genetics)
• Nitric Oxide Synthase Type III
• Phosphoproteins (genetics)
• Phosphorylation
• Rats
• Rats, Inbred Dahl
• Receptors, LDL (genetics)
• Receptors, Oxidized LDL
• Scavenger Receptors, Class E
• Transcription Factor RelA
• Transforming Growth Factor beta (genetics)
• Transforming Growth Factor beta1
• Vascular Cell Adhesion Molecule-1 (genetics)
• Vascular Endothelial Growth Factor A (genetics)
• p38 Mitogen-Activated Protein Kinases (metabolism)