Modification of the β-Adrenoceptor Stimulation Pathway in Zucker Obese and Obese Diabetic Rat Myocardium*

Jiang, Cheng; Carillion, Aude; Na, Na; Jong, Audrey De; Feldman, Sarah; Bonnefont‐Rousselot, Dominique; Riou, Bruno; Amour, Julien

doi:10.1097/ccm.0000000000000999

Cited by 21 publications

(33 citation statements)

References 33 publications

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“…The obese ( fa / fa ) Zucker rats exhibited increased body weight, increased heart weight, without a change in LV volume, and unchanged non‐fasted plasma glucose concentrations (Table ); all indicative of metabolic syndrome with concentric hypertrophic remodelling, as observed previously (Bussey et al., ; Jiang et al., ).…”

Section: Resultssupporting

confidence: 75%

“…In some studies, it was not possible to associate the reduced β‐adrenergic responsiveness of the obese heart with a downregulation of the β‐ARs (Carroll et al., ; Ernsberger, Koletsky, Baskin, & Foley, ; Ferron et al., ; Hohl et al., ; Minhas et al., ; Vileigas et al., ), potentially owing to differences in obese animal models and technical approaches. However, in several other studies, using obese Zucker rats, downregulation of β‐ARs was observed (Chatelain et al., ; Jiang et al., ; Strassheim et al., ), as found in our study. Given that we recently showed in Zucker diabetic fatty rats that only the β 1 ‐AR subtype was directly responsible for the contractile responses (Cook et al., ), we only confirmed the reduced expression of the β 1 ‐AR subtype.…”

Section: Discussionsupporting

confidence: 76%

“…Higher levels of muscle (Agapitov, Correia, Sinkey, & Haynes, ; Huggett et al., ) and cardiac (Thaung, Baldi et al., ) sympathetic nerve activity indicate a systemic sympathetic overdrive, but importantly, increased sympathetic input directly to the heart. Consequently, several studies have demonstrated decreased β‐adrenoceptor (β‐AR) expression in, and reduced β‐AR responsiveness of, the heart in obesity (Bass & Ritter, ; Bunag, Tomita, & Krizsan, ; Chatelain et al., ; Jiang et al., ; Sherwood, Hill, Blumenthal, Johnson, & Hinderliter, ; Strassheim, Houslay, & Milligan, ), with similar reports in diabetes (Cook, Bussey, Mellor, Cragg, & Lamberts, ; Dincer et al., ; Dincer, Onay, Ari, Ozcelikay, & Altan, ; Lamberts et al., ; Thaung, Baldi et al., ).…”

Section: Introductionmentioning

confidence: 76%

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Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

Bussey

Thaung

Hughes

et al. 2018

Experimental Physiology

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The obesity epidemic impacts heavily on cardiovascular health, in part owing to changes in cardiac metabolism. AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis in the heart and is regulated by β-adrenoceptors (β-ARs) in normal conditions. In obesity, chronic sympathetic overactivation leads to impaired cardiac β-AR responsiveness, although it is unclear whether AMPK signalling, downstream of β-ARs, contributes to this dysfunction. Therefore, we aimed to determine whether reduced AMPK signalling is responsible for the reduced β-AR responsiveness in obesity. In isolated hearts of lean and obese Zucker rats, we tested β-AR responsiveness to the β -AR agonist isoprenaline (ISO, 1 × 10 to 5 × 10 m) in the absence and presence of the AMPK inhibitor, compound C (CC, 10 μm). The β -AR expression and AMPK phosphorylation were assessed by Western blot. β-Adrenergic responsiveness was reduced in the hearts of obese rats (logEC of ISO-developed pressure dose-response curves: lean -8.53 ± 0.13 × 10 m versus obese -8.35 ± 0.10 × 10 m ; P < 0.05 lean versus obese, n = 6 per group). This difference was not apparent after AMPK inhibition (logEC of ISO-developed pressure curves: lean CC -8.19 ± 0.12 × 10 m versus obese CC 8.17 ± 0.13 × 10 m, P < 0.05, n = 6 per group). β -Adrenergic receptor expression and AMPK phosphorylation were reduced in hearts of obese rats (AMPK at Thr : lean 1.73 ± 0.17 a.u. versus lean CC 0.81 ± 0.13 a.u., and obese 1.18 ± 0.09 a.u. versus obese CC 0.81 ± 0.16 a.u., P < 0.05, n = 6 per group). Thus, a direct functional link between β-adrenergic responsiveness and AMPK signalling in the heart exists, and AMPK might be an important target to restore the reduced cardiac β-adrenergic responsiveness in obesity.

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Section: Resultssupporting

confidence: 75%

Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 76%

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Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

Bussey

Thaung

Hughes

et al. 2018

Experimental Physiology

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“…Second, we employed an animal model of type-1 diabetes and we studied only short term effects of diabetes and without insulin treatment. This model requires careful extrapolation to human diabetes, particularly type 2 diabetes although it is considered to be a well-established and reliable model for diabetes mellitus [44]. Third, analysis of gene expression using a microarray has its own limitations related to tissue selection, presentation and interpretation of vast amounts of data.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy

Carillion

Feldman

et al. 2017

PLoS ONE

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BackgroundIn the diabetic heart the β-adrenergic response is altered partly by down-regulation of the β1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the β3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their “pleiotropic” effects. The objective of our study was to investigate the role of statin treatment on β-adrenergic dysfunction in diabetic rat cardiomyocytes.Methodsβ-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline ± SD.ResultsAtorvastatin restored the impaired positive inotropic effect of β-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the β-adrenergic pathway and corrected the protein expression of β1-adrenoceptor and β1/β3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the β-adrenoceptor response.ConclusionsAtorvastatin restored the positive inotropic effect of the β-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the β-adrenergic signaling pathway, particularly through the NOS pathway.

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“…Animals were fed with normal rat chow containing 10% of calories from fat, 67% from carbohydrates, and 23% from proteins, 2.791 kcal/g (A04-10, SAFE, Augy, France). A proportion of these animals were used in another experimental study assessing the β-adrenergic function of the myocardium [19]. …”

Section: Methodsmentioning

confidence: 99%

Diaphragmatic function is enhanced in fatty and diabetic fatty rats

Jong

Carreira

et al. 2017

PLoS ONE

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BackgroundObesity is associated with a decrease in mortality in the intensive care unit (ICU) (the "obesity paradox"). We hypothesized that obesity may paradoxically improve diaphragmatic function.MethodsDiaphragm contractility was prospectively recorded in vitro in adult male Zucker lean (control), fatty, and diabetic fatty rats, at rest, after 12h mechanical ventilation and after fatigue. We analyzed diaphragm morphology, cytokines, and protein expression of the protein kinase signaling pathways.ResultsDiaphragm active-force (AF) was higher in fatty (96±7mN.mm-2,P = 0.02) but not in diabetic fatty rats (90±17mN.mm-2) when compared with controls (84±8mN.mm-2). Recovery from fatigue was improved in fatty and diabetic fatty groups compared with controls. Ventilator-induced diaphragmatic dysfunction was observed in each group, but AF remained higher in fatty (82±8mN.mm-2,P = 0.03) compared with controls (70±8mN.mm-2). There was neutral lipid droplet accumulation in fatty and diabetic fatty. There were shifts towards a higher cross-sectional-area (CSA) of myosin heavy chain isoforms (MyHC)-2A fibers in fatty and diabetic fatty compared with control rats (P = 0.002 and P<0.001, respectively) and a smaller CSA of MyHC-2X in fatty compared with diabetic fatty and control rats (P<0.001 and P<0.001, respectively). The phosphorylated total-protein-kinase-B (pAKT)/AKT ratio was higher in fatty (182±58%,P = 0.03), but not in diabetic fatty when compared with controls and monocarboxylate-transporter-1 was higher in diabetic fatty (147±36%,P = 0.04), but not in fatty.ConclusionsDiaphragmatic force is increased in Zucker obese rats before and after mechanical ventilation, and is associated with activation of AKT pathway signaling and complex changes in morphology.

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Modification of the β-Adrenoceptor Stimulation Pathway in Zucker Obese and Obese Diabetic Rat Myocardium*

Abstract: The positive inotropic effect of β-adrenoceptor stimulation is slightly decreased in Zucker obese rats and was more markedly decreased in Zucker diabetic rats. These decreases are mainly related to β1-adrenoceptor down-regulation.

Cited by 21 publications

References 33 publications

Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy

Diaphragmatic function is enhanced in fatty and diabetic fatty rats

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