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Enhanced expression of β3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase.

Abstract：

BACKGROUND:β1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. β3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. METHODS AND RESULTS:Mice with cardiac myocyte-specific expression of human β3-AR (β3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). β3-TG and WT had similar morphometric and hemodynamic parameters at baseline. β3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in β3-TG mice, which also had less re-expression of fetal genes and transforming growth factor β1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of β3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, β3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. CONCLUSIONS:Cardiac-specific overexpression of β3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.

journal_name

Circulation

journal_title

Circulation

authors

Belge C,Hammond J,Dubois-Deruy E,Manoury B,Hamelet J,Beauloye C,Markl A,Pouleur AC,Bertrand L,Esfahani H,Jnaoui K,Götz KR,Nikolaev VO,Vanderper A,Herijgers P,Lobysheva I,Iaccarino G,Hilfiker-Kleiner D,Tavernier G,La

doi

10.1161/CIRCULATIONAHA.113.004940

subject

Has Abstract

pub_date

2014-01-28 00:00:00

pages

451-62

issue

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.113.004940

journal_volume

129

pub_type

杂志文章

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Enhanced expression of β3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase.