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Title
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Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the -adrenoreceptor
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Author
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Abstract
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| Stimulation of the â-adrenergic system is important in the pathological response to sustained cardiac stress, forming the rationale for the use of â-blockers in heart failure. The â3-adrenoreceptor (AR) is thought to couple to the inhibitory G-protein, Gi, with downstream signaling through nitric oxide, although its role in the heart remains controversial. In this study, we tested whether lack of â3-AR influences the myocardial response to pressure-overload. Baseline echocardiography in mice lacking â3-AR (â3−/−) compared to wild type (WT) showed mild LV hypertrophy at 8 weeks that worsened as they aged. â3−/− 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, â3−/− mice also had greater LV dilation, myocyte hypertrophy and enhanced fibrosis. NOS activity declined in â3−/−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 â3−/−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 â3−/− mice from worsened remodeling after TAC, and lowered NOS-dependent superoxide. Thus, lack of â3-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 â3-AR in modulating oxidative stress and adverse remodeling in the failing heart. |
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Language
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English
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Source (journal)
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Journal of molecular and cellular cardiology. - London
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Publication
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London
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2009
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ISSN
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0022-2828
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DOI
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10.1016/J.YJMCC.2009.06.005
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Volume/pages
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47
:5
(2009)
, p. 576-585
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ISI
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000271108000004
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Full text (Publisher's DOI)
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