Differential cardioprotective/cardiotoxic effects mediated by β-adrenergic receptor subtypes

Bernstein, Daniel; Fajardo, Giovanni; Zhao, Mingming; Urashima, Takashi; Powers, Jennifer; Berry, Gerald J.; Kobilka, Brian K.

doi:10.1152/ajpheart.00005.2005

Cited by 86 publications

(75 citation statements)

References 34 publications

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“…Most experiments used sixth- and seventh-generation congenic male C57BL/6J mice, age 10-12 weeks. Mice with KO of β1-ARs or β2-ARs were a generous gift of Daniel Bernstein (Stanford University, Stanford, California, USA) (75). Animal care and use in these experiments was approved by the Animal Care Committees at the San Francisco Veterans Affairs Medical Center and the University of South Dakota (Vermillion, South Dakota, USA).…”

Section: Methodsmentioning

confidence: 99%

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

OʼConnell

Swigart²,

Rodrigo

et al. 2006

Journal of Clinical Investigation

130

139

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An α 1 -adrenergic receptor (α 1 -AR) antagonist increased heart failure in the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT), but it is unknown whether this adverse result was due to α 1 -AR inhibition or a nonspecific drug effect. We studied cardiac pressure overload in mice with double KO of the 2 main α 1 -AR subtypes in the heart, α 1A (Adra1a) and α 1B (Adra1b). At 2 weeks after transverse aortic constriction (TAC), KO mouse survival was only 60% of WT, and surviving KO mice had lower ejection fractions and larger end-diastolic volumes than WT mice. Mechanistically, final heart weight and myocyte cross-sectional area were the same after TAC in KO and WT mice. However, KO hearts after TAC had increased interstitial fibrosis, increased apoptosis, and failed induction of the fetal hypertrophic genes. Before TAC, isolated KO myocytes were more susceptible to apoptosis after oxidative and β-AR stimulation, and β-ARs were desensitized. Thus, α 1 -AR deletion worsens dilated cardiomyopathy after pressure overload, by multiple mechanisms, indicating that α 1 -signaling is required for cardiac adaptation. These results suggest that the adverse cardiac effects of α 1 -antagonists in clinical trials are due to loss of α 1 -signaling in myocytes, emphasizing concern about clinical use of α 1 -antagonists, and point to a revised perspective on sympathetic activation in heart failure.

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Section: Methodsmentioning

confidence: 99%

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

OʼConnell

Swigart²,

Rodrigo

et al. 2006

Journal of Clinical Investigation

130

139

View full text Add to dashboard Cite

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“…−/− mice with a C57BL/6 background as described previously [5,10]. Islets were isolated from adult mice using collagenase P as described previously [11,12].…”

Section: Introductionmentioning

confidence: 99%

A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and β-arrestin 1

Wang

Dong

et al. 2014

Diabetologia

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Aims/hypothesis Somatostatin secretion from islet delta cells plays an important role in regulating islet function and is tightly controlled by environmental changes. Activation of the adrenergic system promoted somatostatin secretion from islet delta cells; however, the role of the adrenergic system in regulating somatostatin content and transcription has not been defined. An imbalance between the somatostatin content and its secretion may cause dysfunctions in the islet delta cells. We have investigated the role of the adrenergic system in the modulation of somatostatin content and transcription in pancreatic delta cells and the detailed underlying mechanisms of this regulation. Methods The stress hormone adrenaline (epinephrine), specific adrenergic agonists or specific adrenergic antagonists were applied to islets from either wild-type or specific adrenergic receptor knockout mice and pancreatic delta cell lines to investigate their effects on somatostatin content and transcription. The GloSensor assay, quantitative real-time PCR, western blots and the dual luciferase assay were used to monitor the cAMP level, somatostatin expression, activations of kinases and transcriptional factors. Arrb1 knockout mice, specific Creb or Pax6 mutations and specific kinase inhibitors were used to dissect the signalling pathway. Results Adrenaline and isoprenaline increased somatostatin content and transcription through the activation of β1-/β2-adrenergic receptors (β1-/β2ARs). The somatostatin content in β1AR−/− (Adrb1/Adrb2 knockout) mice was 50% lower than in β1AR +/+ /β2AR +/+ mice. Two parallel signalling pathways, Gs-cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB) and β-arrestin 1-extracellular signal-related kinase (ERK)-paired box protein 6 (PAX6), cooperatively regulated isoprenaline-induced somatostatin transcription. Conclusions/interpretation A stress pathway increased somatostatin content and transcription through β-adrenergic agonism. β-Arrestin1, ERK and PAX6 are important pancreatic delta cell regulators in addition to cAMP, PKA and CREB. Dysfunction of β-adrenergic agonism may impair pancreatic delta cell function.

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“…For example, impaired ␤-AR stimulation with decreased expression and coupling of ␤-AR subtypes is a hallmark of heart failure (15). Doxorubicin administration to ␤2-AR mutant mice results in altered Erk1͞2 activation and decreased contractile function (16). Mice overexpressing MEK1, an upstream activator of Erk1͞2, display enhanced cardiac contractility (17).…”

mentioning

confidence: 99%

erbB2 is required for G protein-coupled receptor signaling in the heart

Negro

Brar

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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erbB2͞Her2, a ligandless receptor kinase, has pleiotropic effects on mammalian development and human disease. The absence of erbB2 signaling in cardiac myocytes results in dilated cardiomyopathy in mice, resembling the cardiotoxic effects observed in a subset of breast cancer patients treated with the anti-Her2 antibody herceptin. Emerging evidence suggests that erbB2 is pivotal for integrating signaling networks involving multiple classes of extracellular signals. However, its role in G protein-coupled receptor (GPCR) signaling remains undefined. Because the activation of the MAPK pathway through GPCR signaling is important for cardiac homeostasis, we investigated whether erbB2 is required for GPCR-mediated MAPK signaling in wild-type and heart-specific erbB2 mutant mice. Here we demonstrate that erbB2, but not EGF receptor, is essential for MAPK activation induced by multiple GPCR agonists in cardiac myocytes. erbB2 is immunocomplexed with a GPCR in vivo and is transactivated after ligand treatment in vitro. Coexpression of erbB2 with GPCRs in heterologous cells results in ligand-dependent complex formation and MAPK activation. Furthermore, MAPK activation and cardiac contractility are markedly impaired in heart-specific erbB2 mutants infused with a GPCR agonist. These results reveal an essential mechanism requiring erbB2 as a coreceptor for GPCR signaling in the heart. The obligatory role of erbB2 in GPCR-dependent signaling may also be important in other cellular systems.MAPK ͉ cardiac myocytes ͉ erbB2 mutants

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Differential cardioprotective/cardiotoxic effects mediated by β-adrenergic receptor subtypes

Cited by 86 publications

References 34 publications

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and β-arrestin 1

erbB2 is required for G protein-coupled receptor signaling in the heart

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