Disruption of type 5 adenylyl cyclase prevents β-adrenergic receptor cardiomyopathy: A novel approach to β-adrenergic receptor blockade

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Abstract

β-Adrenergic receptor (β-AR) blockade is widely used to treat heart failure, since the adverse effects of chronic β-AR stimulation are central to the pathogenesis of this disease state. Transgenic (Tg) mice, where β-AR signaling is chronically enhanced by overexpression of cardiac β2-ARs, is a surrogate for this mechanism, since these mice develop cardiomyopathy as reflected by reduced left ventricular (LV) function, increased fibrosis, apoptosis, and myocyte hypertrophy. We hypothesized that disruption of type 5 adenylyl cyclase (AC5), which is in the β-AR signaling pathway in the heart, but exerts only a minor β-AR blocking effect, could prevent the cardiomyopathy in β2-AR Tg mice without the negative effects of full β-AR blockade. Accordingly, we mated β2-AR Tg mice with AC5 knockout (KO) mice. The β2-AR Tg × AC5 KO bigenic mice prevented the cardiomyopathy as reflected by improved LV ejection fraction, reduced apoptosis, fibrosis, and myocyte size and preserved exercise capacity. The rescue was not simply due to a β-blocking effect of AC5 KO, since neither baseline LV function nor the response to isoproterenol was diminished substantially compared with the negative inotropic effects of β-blockade. However, AC5 disruption in β2-AR Tg activates the antioxidant, manganese superoxide dismutase, an important mechanism protecting the heart from cardiomyopathy. These results indicate that disruption of AC5 prevents the cardiomyopathy induced by chronically enhanced β-AR signaling in mice with overexpressed β2-AR, potentially by enhancing resistance to oxidative stress and apoptosis, suggesting a novel, alternative approach to β-AR blockade.

Original languageEnglish (US)
Pages (from-to)H1521-H1528
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume307
Issue number10
DOIs
StatePublished - Nov 15 2014

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Oxidative stress
  • β-adrenergic receptor signaling

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