Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor.

Abstract

Stimulation of the beta-adrenergic system is important in the pathological response to sustained cardiac stress, forming the rationale for the use of beta-blockers in heart failure. The beta3-adrenoreceptor (AR) is thought to couple to the inhibitory G-protein, G(i), with downstream signaling through nitric oxide, although its role in the heart remains controversial. In this study, we tested whether lack of beta3-AR influences the myocardial response to pressure-overload. Baseline echocardiography in mice lacking beta3-AR (beta3(-/-)) compared to wild type (WT) showed mild LV hypertrophy at 8 weeks that worsened as they aged. beta3(-/-) mice had much greater mortality after transverse aortic constriction (TAC) than WT controls. By 3 weeks of TAC, systolic function was worse. After 9 weeks of TAC, beta3(-/-) mice also had greater LV dilation, myocyte hypertrophy and enhanced fibrosis. NOS activity declined in beta3(-/-)TAC hearts after 9 weeks, and total and NOS-dependent superoxide rose, indicating heightened oxidative stress and NOS uncoupling. The level of eNOS phosphorylation in beta3(-/-)TAC hearts was diminished, and nNOS and iNOS expression levels were increased. GTP cyclohydrolase-1 expression was reduced, although total BH4 levels were not depleted. 3 weeks of BH4 treatment rescued beta3(-/-) mice from worsened remodeling after TAC, and lowered NOS-dependent superoxide. Thus, lack of beta3-AR signaling exacerbates cardiac pressure-overload induced remodeling and enhances NOS uncoupling and consequent oxidant stress, all of which can be rescued with exogenous BH4. These data suggest a cardioprotective role for the beta3-AR in modulating oxidative stress and adverse remodeling in the failing heart.

• Authors: An L Moens, Jordan S Leyton-Mange, Xiaolin Niu, Ronghua Yang, Oscar Cingolani, Elisabeth K Arkenbout, Hunter C Champion, Djahida Bedja, Kathleen L Gabrielson, Juan Chen, Yong Xia, Ashley B Hale, Keith M Channon, Marc K Halushka, Norman Barker, Floris L Wuyts, Pawel M Kaminski, Michael S Wolin, David A Kass, Lili A Barouch
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 47 Issue 5 Pg. 576-85 (Nov 2009) ISSN: 1095-8584 [Electronic] England
• PMID: 19766235 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Adrenergic, beta-3
• Superoxides
• Biopterins
• Nitric Oxide Synthase
• sapropterin

Topics

• Age Factors
• Animals
• Biopterins (analogs & derivatives, therapeutic use)
• Blotting, Western
• Cardiomyopathies (genetics, pathology)
• Echocardiography
• Hypertrophy, Left Ventricular (drug therapy, genetics, pathology)
• Male
• Mice
• Mice, Mutant Strains
• Nitric Oxide Synthase (metabolism)
• Oxidative Stress (genetics, physiology)
• Receptors, Adrenergic, beta-3 (genetics, physiology)
• Superoxides (metabolism)
• Vasoconstriction (physiology)
• Ventricular Remodeling (drug effects, genetics, physiology)