Testosterone modulation of cardiac β-adrenergic signals in a rat model of heart failure

Sun, Jing; Fu, Lu; Tang, Xianling; Han, Ying; Ma, Dan; Cao, Junxian; Kang, Ningning; Ji, Hongfei

doi:10.1016/j.ygcen.2011.04.019

Cited by 31 publications

(20 citation statements)

References 39 publications

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“…Our data suggest that in early chronic Dox-cardiotoxicity, β 3 -AR could not play a major role in the cardiac alterations. At a later stage (d70), we observed a decreased β 3 -AR protein expression in Dox-CM hearts albeit another team reported an overexpression of β 3 -AR protein at the same stage [11]. Several hypotheses could explain those discrepancies.…”

Section: Discussionmentioning

confidence: 64%

“…Very few studies reported long term effects of Dox-treatment and data on mortality and ascites are very heterogeneous. Whereas a study observed 50% mortality rate 6 weeks after the last Dox-injection, associated with a very large amount of ascites [25] others did not observed mortality eight weeks after the last Dox-injection [11]. Also, others did not reported mortality and observed a decrease in ascites amount between days 40 and 70 [26].…”

Section: Discussionmentioning

confidence: 96%

“…However, at the present time, only few studies have examined the role of cardiac β 1 - and β 2 -adrenoceptor (β-AR) subtypes in the pathogenesis of Dox-cardiotoxicity [9], [10] and only one study, at late-onset Dox-CM, assessed β 3 -AR subtype [11], which is recently described as a new target for some β-blockers such as nebivolol [12], [13]. Despite this lack in experimental data, some clinical studies investigated β-blocker therapies in Dox-CM.…”

Section: Introductionmentioning

confidence: 99%

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Increased Beta2-Adrenoceptors in Doxorubicin-Induced Cardiomyopathy in Rat

et al. 2013

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BackgroundThe toxicity of doxorubicin, leading to an irreversible heart failure, limits its use as chemotherapeutic agent. The beneficial effects of early administration of β-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of β-adrenoceptors (β-ARs). This study aimed to identify a putative target (β-AR and/or its effectors) at the early phase of a chronic doxorubicin-induced cardiomyopathy (Dox-CM) in a rat model.MethodologyDox-CM was induced by six doxorubicin injections (cumulative dose: 15 mg.kg−1) and validated by echocardiography and left ventricle (LV) catheterization. The β-AR protein expressions in LV were evaluated by western-blot at days 35 (d35) and 70 (d70) after the first doxorubicin injection. Ex vivo cardiac contractility (dP/dtmax, dP/dtmin) was evaluated on isolated heart in response to specific β-AR stimulations at d35.ResultsAt d35, Dox-CM hearts were characterized by mild LV systolic and diastolic dysfunctions, which were exacerbated at d70. In Dox-CM hearts, β3-AR expression was only decreased at d70 (-37±8%). At d35, β1-AR expression was decreased by 68±6%, but ex vivo β1-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. β2-AR expression was increased both at d35 (+58±22%) and d70 (+174±35%), with an increase of ex vivo β2-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect β2-AR response in Dox-CM hearts, suggesting a decoupling of β2-AR to Gi protein.ConclusionThis study highlights the β1/β2-AR imbalance in early Dox-CM and reveals the important role that β2-AR/Gi coupling could play in this pathology. Our results suggest that β2-AR could be an interesting target at early stage of Dox-CM.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Increased Beta2-Adrenoceptors in Doxorubicin-Induced Cardiomyopathy in Rat

et al. 2013

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“…Testosterone replacement therapy has been shown to modulate the cardiac B-adrenergic system, reduce wall stress and left ventricular end-diastolic pressure, promote angiogenesis, and improve cardiac function following myocardial infarction (MI; Nahrendorf et al 2003, Sun et al 2011, Chen et al 2012. However, experiments investigating how testosterone affects mitochondrial network proteins and functions post-MI remain scarce.…”

Section: Introductionmentioning

confidence: 99%

Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction

Wang¹,

Yang²,

Sun³

et al. 2015

Journal of Endocrinology

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Testosterone can affect cardiovascular disease, but its effects on mitochondrial dynamics in the post-infarct myocardium remain unclear. To observe the effects of testosterone replacement, a rat model of castration-myocardial infarction (MI) was established by ligating the left anterior descending coronary artery 2 weeks after castration with or without testosterone treatment. Expression of mitochondrial fission and fusion proteins was detected by western blot and immunofluorescence 14 days after MI. Cardiac function, myocardial inflammatory infiltration and fibrosis, cardiomyocyte apoptosis, mitochondrial microstructure, and ATP levels were also assessed. Compared with MI rats, castrated rats showed aggravated mitochondrial and myocardial insults, including mitochondrial swelling and disordered arrangement; loss of cristae, reduced mitochondrial length; decreased ATP levels; cardiomyocyte apoptosis; and impaired cardiac function. Results of western blotting analyses indicated that castration downregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) and mitofusin 2, but upregulated dynamin-related protein 1. The results were also supported by results obtained using immunofluorescence. However, these detrimental effects were reversed by testosterone supplementation, which also elevated the upstream AMP-activated protein kinase (AMPK) activation of PGC1A. Thus, testosterone can protect mitochondria in the post-infarct myocardium, partly via the AMPK-PGC1A pathway, thereby decreasing mitochondrial dysfunction and cardiomyocyte apoptosis. The effects of testosterone were confirmed by the results of ELISA analyses.

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“…12 Alterations in the β-adrenergic receptor signaling system were also seen after testosterone treatment in an animal model of heart failure. 13 …”

mentioning

confidence: 99%

Oxandrolone Coadministration Does Not Alter Plasma Propranolol Concentrations in Severely Burned Pediatric Patients

Guillory

Herndon

Silva

et al. 2017

Journal of Burn Care & Research

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The systemic impact of severe burn injury results in a variety of disorders that require therapeutic intervention. Propranolol, a nonselective β1, β2-adrenergic receptor antagonist, reduces resting heart rate and cardiac work caused by elevated circulating catecholamines. Oxandrolone, a testosterone mimetic, promotes protein synthesis and anabolism to counter muscle wasting. Coadministration of these drugs is expected to synergistically improve patient outcomes. Testosterone administration is known to alter β-adrenergic receptor-mediated signaling. Here, we determined whether the coadministration of oxandrolone alters plasma propranolol concentrations. Ninety-two pediatric patients with burns covering ≥30% of the TBSA were enrolled in this institutional review board-approved study and randomized to receive propranolol (n = 49) or oxandrolone + propranolol (n = 43). Plasma propranolol concentrations were determined following two dosing strategies: Q6 (liquid formulation; n = 86) and Q24 (extended-release capsule; n = 22). Samples were drawn before drug administration and at regular intervals throughout the next two dosing periods. Heart rate and blood pressure were recorded throughout the study. Propranolol half-life was 3.3 hours for the Q6 drug dosing frequency (P < .0001) and 11.2 hours for the Q24 strategy (P < .0001). Percentage of predicted heart rate declined by 2.8% for each doubling of the propranolol concentration in the Q6 dosing schedule (P < .0001). Percentage of predicted heart rate declined by 2.5% for each doubling of propranolol concentration on the Q24 dosing schedule (P < .0001). Maximum and minimum propranolol plasma concentrations were similar with either dosing regimen. The addition of oxandrolone did not affect any of the measured parameters. Oxandrolone coadministration does not alter propranolol’s plasma concentration, half-life, or effect on heart rate. This study is registered at clincialtrials.gov: NCT00675714.

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Testosterone modulation of cardiac β-adrenergic signals in a rat model of heart failure

Cited by 31 publications

References 39 publications

Increased Beta2-Adrenoceptors in Doxorubicin-Induced Cardiomyopathy in Rat

Increased Beta2-Adrenoceptors in Doxorubicin-Induced Cardiomyopathy in Rat

Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction

Oxandrolone Coadministration Does Not Alter Plasma Propranolol Concentrations in Severely Burned Pediatric Patients

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