Altered Contractile Response due to Increased β3-Adrenoceptor Stimulation in Diabetic Cardiomyopathy

Amour, Julien; Loyer, Xavier; Guen, Morgan Le; Mabrouk, N.; David, Jean; Camors, Emmanuel; Carusio, Nunzia; Vivien, Benoît; Andriantsitohaina, Ramaroson; Heymes, Christophe; Riou, Bruno

doi:10.1097/01.anes.0000278909.40408.24

Cited by 61 publications

(80 citation statements)

References 41 publications

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“…In this study, our attention was focused on NOS2 and NOS1 in the heart. Previous studies suggested that NOS2 was solely responsible for β3-AR-induced NO production [41]. However, new research indicates that NOS1 also plays a key role in β3-AR signaling [16].…”

Section: Discussionmentioning

confidence: 99%

Aerobic Exercise Inhibits Sympathetic Nerve Sprouting and Restores β-Adrenergic Receptor Balance in Rats with Myocardial Infarction

Cui

Cai

et al. 2014

PLoS ONE

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BackgroundCardiac sympathetic nerve sprouting and the dysregulation of β-adrenergic receptor (β-AR) play a critical role in the deterioration of cardiac function after myocardial infarction (MI). Growing evidence indicates that exercise provides protection against MI. The aims of this study were to investigate whether aerobic exercise following MI could inhibit sympathetic nerve sprouting and restore the balance of β3-AR/β1-AR.MethodsMale Sprague-Dawley rats were divided into three groups: sham-operated control group (SC), MI group (MI), and MI with aerobic exercise group (ME). The rats in ME group were assigned to 8 weeks of exercise protocol (16 m/min, 50 min/d, 5 d/wk). The expression of nerve growth factor (NGF), the sympathetic nerve marker-tyrosine hydroxylase (TH), the nerve sprouting marker-growth associated protein 43 (GAP43), and β1- and β2-AR expression in the peri-infarct area of the left ventricle (LV) were measured by Western blot and immunohistochemistry, while β3-AR expression was determined by Western blot and immunofluorescence. Endothelial nitric oxide synthase (NOS2), phospho-NOS2 (p-NOS2), and neuronal nitric oxide synthase (NOS1) were measured by Western blot.ResultsMI increased LV end-diastolic pressure (LVEDP), and decreased LV systolic pressure (LVSP). Compared with the MI group, aerobic exercise significantly decreased LVEDP and increased LVSP. The protein expression of TH, GAP43 and NGF was significantly increased after MI, which was normalized by exercise. Compared with the SC group, the ratios of β2-AR/β1-AR and β3-AR/β1-AR were elevated in the MI group, and the protein expression of β3-AR and NOS1 increased after MI. Compared with the MI group, the ratios of β2-AR/β1-AR and β3-AR/β1-AR were normalized in the ME group, while the protein expression of β3-AR and NOS1 significantly increased, and NOS2 was activated by exercise.ConclusionsAerobic exercise inhibits cardiac sympathetic nerve sprouting, restores β3-AR/β1-AR balance and increases β3-AR expression through the activation of NOS2 and NOS1 after myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

Aerobic Exercise Inhibits Sympathetic Nerve Sprouting and Restores β-Adrenergic Receptor Balance in Rats with Myocardial Infarction

Cui

Cai

et al. 2014

PLoS ONE

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“…Six-week-old male Wistar rats (Janvier, Le Genest-St Isle, France) were divided into a healthy group and a diabetic group. Diabetes mellitus was induced by streptozotocin (65 mg.kg -1 , single intravenous bolus; Sigma-Aldrich, L’Isle d’Abeau Chesnes, France) as previously described [6]. After 6 weeks, rats from healthy or diabetic groups were assigned to orally receive over 15 days either vehicle or atorvastatin (50 mg.kg -1 day-1 per os, Pfizer, Paris, France) [26].…”

Section: Methodsmentioning

confidence: 99%

“…The left ventricular papillary muscles were carefully excised and suspended vertically in a Krebs-Henseleit bicarbonate buffer solution at 29°C and bubbled with 95% O2 and 5% CO 2 as previously described [6]. The papillary muscles were stimulated at 12 Hz for 60-min stabilization period at the initial muscle length at the apex of length–active isometric tension curve (L max ).…”

Section: Methodsmentioning

confidence: 99%

“…In intensive care units, diabetic patients represent usually 30% of the population and they are known to be at increased risk of cardiac overload and mortality [4]. The β-adrenergic pathway plays a crucial role for maintaining cardiac output and the response to β-adrenergic stimulation is known to be altered in the diabetic cardiomyopathy [5,6]. The prime mechanisms of diabetic cardiomyopathy appear to be hyperglycemia and advanced generation of glycation end-products, leading to endothelial dysfunction and fibrosis and increase in inflammation and oxidative stress [7,8].…”

Section: Introductionmentioning

confidence: 99%

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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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“…The negative inotropic effect of β3-AR stimulation involves NOS/NO signaling [2,5,10,11], and while it was initially thought to be due to endothelial NOS (eNOS), new data has shown that neuronal NOS (nNOS) also plays a key role [12–15]. In mice with nNOS genetically deleted or acutely inhibited, β3-AR-dependent cardiac protection, NO generation, and NOS downstream signaling are lacking in failing mouse myocardium [10,11].…”

Section: Introductionmentioning

confidence: 99%

Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation

Watts

Sepulveda

Cingolani

et al. 2013

Journal of Molecular and Cellular Cardiology

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Rationale Stimulation of β3-adrenoreceptors (β3-AR) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nNOS) dependent manner. nNOS can be regulated by post-translational modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, the role of phosphorylation of these residues in cardiomyocytes and β3-AR protective signaling has yet to be explored. Objective We tested the hypothesis that β3-AR regulation of myocyte stress requires changes in nNOS activation mediated by differential nNOS phosphorylation. Methods and results Endothelin (ET-1) or norepinephrine induced hypertrophy in rat neonatal ventricular cardiomyocytes (NRVMs) was accompanied by increased β3-AR gene expression. Co-administration of the β3-AR agonist BRL-37433 (BRL) reduced cell size and reactive oxygen species (ROS) generation, while augmenting NOS activity. BRL-dependent augmentation of NOS activity and ROS suppression due to NE were blocked by inhibiting nNOS (L-VNIO). BRL augmented nNOS phosphorylation at Ser1412 and dephosphorylation at Ser847. Cells expressing constitutively dephosphorylated Ser1412A or phosphorylated Ser847D nNOS mutants displayed reduced nNOS activity and a lack of BRL modulation. BRL also failed to depress ROS from NE in cells with nNOS-Ser847D. Inhibiting Akt decreased BRL-induced nNOS-Ser1412 phosphorylation and NOS activation, whereas Gi/o blockade blocked BRL-regulation of both post-translational modifications, preventing enhancement of NOS activity and ROS reduction. BRL resulted in near complete dephosphorylation of Ser847 and a moderate rise in Ser1412 phosphorylation in mouse myocardium exposed to chronic pressure-overload. Conclusion β3-AR regulates myocardial NOS activity and ROS via activation of nNOS involving reciprocal changes in phosphorylation at two regulatory sites. These data identify a novel and potent anti-oxidant and anti-hypertrophic pathway due to nNOS post-translational modification that is coupled to β3-AR receptor stimulation.

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Altered Contractile Response due to Increased β3-Adrenoceptor Stimulation in Diabetic Cardiomyopathy

Abstract: beta3-Adrenoceptor is involved in altered positive inotropic response to beta-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by NOS1-derived nitric oxide in diabetic cardiomyocyte.

Cited by 61 publications

References 41 publications

Aerobic Exercise Inhibits Sympathetic Nerve Sprouting and Restores β-Adrenergic Receptor Balance in Rats with Myocardial Infarction

Aerobic Exercise Inhibits Sympathetic Nerve Sprouting and Restores β-Adrenergic Receptor Balance in Rats with Myocardial Infarction

Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy

Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation

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