Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

Abstract

451H emodynamic overload and ischemic or oxidative stress promote adverse cardiac remodeling, a leading cause of worsening heart failure.1,2 Most of these pathophysiologic conditions are associated with (and to a certain extent, mediated by) adrenergic stimulation and catecholamines release, resulting in adrenoceptor (AR) activation on different cell types within the myocardium. Among these, cardiac myocyte β1-ARs are classically considered to mediate short-term positive effects on all aspects of myocardial contractility; however, long-term stimulation produces adverse effects on myocardial remodeling, in part through activation of calciumdependent prohypertrophic effects, ultimately associated with cardiomyocyte loss. 3,4 Such maladaptive remodeling is usually accompanied by left ventricle (LV) geometry disruption 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. and interstitial and replacement fibrosis leading to progressive diastolic and systolic heart failure. Deciphering the underlying signaling pathways may lead to new therapeutic strategies that favorably modulate remodeling. The use of β1-AR blockers provided a major advance in this direction, albeit far from totally efficient. 5 The third isotype of β-AR (β3-AR) has classically been considered as a metabolic regulator (eg, by mediating lipolysis in the adipose tissue).6 β3-ARs ...

Exercise attenuates inflammation and limits scar thinning after myocardial infarction in mice

“…The endogenous activation of ␤ 3 ARs was associated with reduced myocardial injury during MI; however, no analysis of fibrosis was provided in this study (8). Moreover, coupling of ␤ 3 ARs to eNOS provided protection from isoproterenol-induced hypertrophy and fibrosis (4). Finally, studies from our own laboratory have revealed that exercise-mediated protective effects on telomere regulation and protection from doxorubicin-induced cardiac damage were mediated by eNOS (82), and eNOS deletion aggravated fibrosis and maladaptive remodeling after pressure overload (30).…”

Loss of Mouse P2Y6 Nucleotide Receptor Is Associated with Physiological Macrocardia and Amplified Pathological Cardiac Hypertrophy

“…of ␤3-adrenoceptors was reported to inhibit hypertrophic response to ISO in vitro and in vivo through endothelial nitricoxide synthase stimulation (28). Third generation ␤-adrenoreceptor blockers such as Nebivolol have further properties including stimulation of NOS and/or ␤3-adrenoceptors (29).…”

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…NPRC, on the other hand, lacks the intracellular guanylate cyclase domain and has been shown to signal to inhibitory guanine nucleotide‐binding protein (inhibitory G protein) 9. Soluble guanylyl cyclase, on the other hand, is activated by nitric oxide and was recently shown to mediate the protective effects of β3‐adrenergic receptor activation on left ventricle (LV) remodeling 10, 11. NP activation, secretion, and signaling in different cell types are summarized in Figure 1.…”