Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice

Beetz, Nadine; Harrison, Michael D.; Brede, Marc; Zong, Xin; Urbanski, Michal J.; Sietmann, Anika; Kaufling, Jennifer; Barrot, Michel; Seeliger, Mathias W.; Vieira-Coelho, Maria Augusta; Hamet, Pavel; Gaudet, Daniel; Šeda, Ondřej; Tremblay, Johanne; Kaldunski, Mary L.; Nüsing, Rolf M.; Szabó, Béla; Jacob, Howard J.; Cowley, Allen W.; Biel, Martin; Stoll, Monika; Broeckel, Ulrich; Hein, Lutz

doi:10.1172/jci38433

Cited by 28 publications

(38 citation statements)

References 46 publications

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“…After thoracotomy, a 7.0 silk suture was placed around a 27-G hypodermic needle to constrict the transverse aorta (TAC). 21,22 TAC mice were compared with nonoperated mice at baseline ("basal").…”

Section: Transverse Aortic Constrictionmentioning

confidence: 99%

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Ablation of Mineralocorticoid Receptors in Myocytes But Not in Fibroblasts Preserves Cardiac Function

et al. 2011

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Abstract-Antagonists of the mineralocorticoid receptor improve morbidity and mortality in patients with severe heart failure. However, the cell types involved in these beneficial effects are only partially known. The aim of this work was to evaluate whether genetic deletion of mineralocorticoid receptors in mouse cardiomyocytes or fibroblasts in vivo is cardioprotective after chronic left ventricular pressure overload. After transverse aortic constriction, mice deficient in myocyte mineralocorticoid receptors but not those deficient in fibroblast mineralocorticoid receptors were protected from left ventricular dilatation and dysfunction. After pressure overload, left ventricular ejection fraction was significantly higher in mice lacking myocyte mineralocorticoid receptors (70.2Ϯ4.4%) as compared with control mice (54.3Ϯ2.5%; PϽ0.01). Myocyte mineralocorticoid receptor-deficient mice showed mild cardiac hypertrophy at baseline, contributing to reduced left ventricular wall tension at baseline and after pressure overload. Cardiac levels of phospho-extracellular signal-regulated kinase 1/2 were higher in myocyte mineralocorticoid receptor-deficient mice than in control mice after pressure overload. Neither fibroblast nor myocyte mineralocorticoid receptor ablation altered the development of cardiac hypertrophy or fibrosis after pressure overload. Both mineralocorticoid receptor mutant mouse strains developed similar degrees of myocyte apoptosis, proinflammatory gene expression, and macrophage infiltration after pressure overload. Thus, mineralocorticoid receptors in cardiac myocytes but not in fibroblasts protect from cardiac dilatation and failure after chronic pressure overload.

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Section: Transverse Aortic Constrictionmentioning

confidence: 99%

“…21,22 Echocardiography was performed at baseline and every 2 weeks for 20 weeks after transverse aortic constriction using a Vivid 7 Dimension (GE Healthcare) echocardiograph equipped with a 14-MHz transducer. Ejection fraction was calculated as described.…”

Section: Hemodynamic Measurements and Echocardiographymentioning

confidence: 99%

Ablation of Mineralocorticoid Receptors in Myocytes But Not in Fibroblasts Preserves Cardiac Function

et al. 2011

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“…Cardiac sections were stained with hematoxylin and eosin. Semithin araldite sections of the lung were stained with methylene blue (11,12). For immunodetection of sonic hedgehog, cryostat sections were incubated with primary antiserum (R&D Systems, Wiesbaden, Germany) followed by an Alexa Fluor 488 secondary antibody (Molecular Probes, Invitrogen, Darmstadt, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Cardiac Function and Blood Glucose-Electrocardiograms were recorded from newborn mice during isoflurane anesthesia (DSI Transoma Medical, TA10EA-F20 transmitters) as described previously (11,15). Recordings were obtained at a sampling frequency of 2 kHz using the ECG module of ADI Chart software (AD Instruments, Castle Hill, Australia).…”

Section: Methodsmentioning

confidence: 99%

α2B-Adrenoceptor Deficiency Leads to Postnatal Respiratory Failure in Mice*

Haubold

Gilsbach

Hein

2010

Journal of Biological Chemistry

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␣ 2 -Adrenoceptors belong to the family of adrenergic receptors, which regulate the neuronal release of norepinephrine as part of a negative feedback loop. Among the ␣ 2 -adrenoceptors, the ␣ 2B -subtype may also influence developmental signaling pathways involved in angiogenesis of the placenta. Thus, the aim of the present study was to determine whether ␣ 2B -adrenoceptors are also involved in other developmental processes beyond placental angiogenesis. Ablation of ␣ 2B -adrenoceptors led to lethality of mutant mice during the first hours after birth. Despite normal breathing and drinking behavior, mutant mice developed cyanosis, which could be traced back to a defect in lung morphology with significantly reduced alveolar volume and thickened interalveolar septi. In ␣ 2B -deficient lungs and in isolated alveolar type II cells, expression of sonic hedgehog (SHH) was significantly increased, resulting in mesenchymal proliferation. In vitro ␣ 2B -adrenoreceptor stimulation suppressed expression of sonic hedgehog and the cell cycle genes cyclin D1 and Ki67. In vivo inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine partially rescued perinatal lethality, lung morphology, and altered gene expression in mutant mice. Thus, ␣ 2B -adrenoceptors in lung epithelia play an important role in suppressing sonic hedgehogmediated proliferation of mesenchymal cells and thus prevent respiratory failure.␣ 2 -Adrenoceptors belong to the family of G protein-coupled receptors that mediate the biological actions of the endogenous catecholamines noradrenaline and adrenaline (1, 2). These receptors were initially identified as presynaptic inhibitory feedback regulators of noradrenaline release from sympathetic or central adrenergic nerve terminals (3, 4). However, ␣ 2 -adrenoceptors have since also been found to mediate a wide spectrum of postsynaptic functions including hypotension and bradycardia, sedation, and analgesia (5-8). In addition to the modulation of physiological functions in the adult organism, the ␣ 2B -receptor subtype also plays an important role during embryonic development (9, 10).Mice lacking functional ␣ 2A -, ␣ 2B -, and ␣ 2C -adrenoceptors on a mixed genetic background died between embryonic days 9.5 and 11.5 from a severe defect in yolk sac and placental development (10). This defect was mostly ascribed to loss of ␣ 2B -adrenoreceptor function as ␣ 2B -deficient mice, which were backcrossed onto a C57BL/6 background, showed a similar defect in placenta vasculogenesis (9).The purpose of the present study was to identify the function of ␣ 2B -adrenoceptors in embryonic and perinatal development in mice. Here we demonstrate that ␣ 2B -deficient mice suffer from an early postnatal defect in lung maturation. In ␣ 2B -deficient lungs, sonic hedgehog (SHH) 2 and its receptor patched were up-regulated, resulting in enhanced mesenchymal proliferation. In vivo inhibition of SHH signaling by the smoothened antagonist cyclopamine partially rescued postnatal lethality and the pulmonary phenotype ass...

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“…5,[26][27][28] Untreated mice served as controls. Blood pressure was determined invasively by telemetry after implantation of pressure transmitters TA11PA-C10 (Data Sciences International) into the left carotid artery as previously described 29 at 2 and 6 weeks after initiation of DOCA treatment.…”

Section: Doca/salt Model and Hemodynamic Measurementsmentioning

confidence: 99%

Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

et al. 2016

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Abstract-Chronic kidney disease has a tremendously increasing prevalence and requires novel therapeutic approaches.Mineralocorticoid receptor (MR) antagonists have proven highly beneficial in the therapy of cardiac disease. The cellular and molecular events leading to cardiac inflammation and remodeling are proposed to be similar to those mediating renal injury. Thus, this study was designed to evaluate and directly compare the effect of MR deletion in endothelial cells on cardiac and renal injury in a model of deoxycorticosterone acetate-induced hypertension. Endothelial MR deletion ameliorated deoxycorticosterone acetate/salt-induced cardiac remodeling. This was associated with a reduced expression of the vascular cell adhesion molecule Vcam1 in MR-deficient cardiac endothelial cells. Ambulatory blood pressure telemetry revealed that the protective effect of MR deletion was independent from blood pressure. Similar to the heart, deoxycorticosterone acetate/salt-induced severe renal injury, including inflammation, fibrosis, glomerular injury, and proteinuria. However, no differences in renal injury were observed between genotypes. In conclusion, MR deletion from endothelial cells ameliorated deoxycorticosterone acetate/salt-induced cardiac inflammation and remodeling independently from alterations in blood pressure but it did not affect renal injury. These findings suggest that the anti-inflammatory mechanism mediating organ protection after endothelial cell MR deletion is specific for the heart versus the kidney.

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Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice

Cited by 28 publications

References 46 publications

Ablation of Mineralocorticoid Receptors in Myocytes But Not in Fibroblasts Preserves Cardiac Function

Ablation of Mineralocorticoid Receptors in Myocytes But Not in Fibroblasts Preserves Cardiac Function

α2B-Adrenoceptor Deficiency Leads to Postnatal Respiratory Failure in Mice*

Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

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