Cardiovascular and Metabolic Alterations in Mice Lacking Both β1- and β2-Adrenergic Receptors

Rohrer, Daniel K.; Chruscinski, Andrzej; Schauble, Eric; Bernstein, Daniel; Kobilka, Brian K.

doi:10.1074/jbc.274.24.16701

Cited by 257 publications

(208 citation statements)

References 43 publications

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“…For this purpose we evaluated the skeletal response to loading by axial compression in Adrb1 À/À , Adrb2 À/À , and Adrb1b2 À/À double knockout mice and we further characterized the mechanisms by which b1-adrenergic receptors and b2-adrenergic receptors may regulate bone mass and microarchitecture. (24) Our results indicate that b1-adrenergic receptors and b2-adrenergic receptors exert opposite effects on bone remodeling through both systemic and local factors.…”

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confidence: 67%

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Deletion of β-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation

Pierroz¹,

Bonnet²,

Bianchi³

et al. 2012

Journal of Bone and Mineral Research

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As they age, mice deficient for the b2-adrenergic receptor (Adrb2 À/À ) maintain greater trabecular bone microarchitecture, as a result of lower bone resorption and increased bone formation. The role of b1-adrenergic receptor signaling and its interaction with b2-adrenergic receptor on bone mass regulation, however, remains poorly understood. We first investigated the skeletal response to mechanical stimulation in mice deficient for b1-adrenergic receptors and/or b2-adrenergic receptors. Upon axial compression loading of the tibia, bone density, cancellous and cortical microarchitecture, as well as histomorphometric bone forming indices, were increased in both Adrb2 À/À and wild-type (WT) mice, but not in Adrb1 À/À nor in Adrb1b2 À/À mice. Moreover, in the unstimulated femur and vertebra, bone mass and microarchitecture were increased in Adrb2 À/À mice, whereas in Adrb1 À/À and Adrb1b2 À/À double knockout mice, femur bone mineral density (BMD), cancellous bone volume/total volume (BV/TV), cortical size, and cortical thickness were lower compared to WT. Bone histomorphometry and biochemical markers showed markedly decreased bone formation in Adrb1b2 À/À mice during growth, which paralleled a significant decline in circulating insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGF-BP3). Finally, administration of the b-adrenergic agonist isoproterenol increased bone resorption and receptor activator of NF-kB ligand (RANKL) and decreased bone mass and microarchitecture in WT but not in Adrb1b2 À/À mice. Altogether, these results demonstrate that b1-and b2-adrenergic signaling exert opposite effects on bone, with b1 exerting a predominant anabolic stimulus in response to mechanical stimulation and during growth, whereas b2-adrenergic receptor signaling mainly regulates bone resorption during aging. ß

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confidence: 67%

“…Adrb1b2 À/À mice were on a mixed 129 SvJ, FVB/N, C57BL/6J genetic background. (24) Mice were maintained under standard non-barrier conditions and had access to mouse chow (RM3; SDS, Surrey, UK) and water ad libitum.…”

Section: Animals and Experimental Proceduresmentioning

confidence: 99%

Deletion of β-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation

Pierroz¹,

Bonnet²,

Bianchi³

et al. 2012

Journal of Bone and Mineral Research

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“…Alteration of gene expression and responsiveness of other receptors and their effectors have been reported in numerous genetic knock out mice. For instance, mice deficient in both β 1 -and β 2 -adrenergic receptors show an exaggerated response to a β 3 agonist [24] as well as enhanced dopamine function was found in 5-HT1B receptor knockout mice [25]. Also, in the absence of nNOS, eNOS was able to somehow change its expression to compensate for the loss of nNOS [26].…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

Teng¹,

Ledent²,

Mustafa³

2008

Journal of Molecular and Cellular Cardiology

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In this study, we looked into possible compensatory changes of other adenosine receptors (AR) in A 2A genetic knockout mice (A2AKO) as well as the functional role of nitric oxide (NO) in A 2A ARmediated vasodilation. Gene expression of ARs from coronary arteries of A 2A AR wild type mice (A2AWT) and A2AKO were studied using real time-PCR. Functional studies were carried out in isolated heart and isolated coronary artery preparations. A 2B AR was found to be 4.5 fold higher in A2AKO than in A2AWT, while A 2A AR expression was absent in A2AKO. There was no difference in A 1 and A 3 ARs between WT and KO animals. The concentration-relaxation curve for adenosine-5′-N-ethylcarboxamide (NECA, non-selective AR agonist) in isolated coronary arterial rings in A2AKO was shifted to the left when compared to A2AWT. The concentration-response curve for A 2B selective agonist (Bay 60-6583) was also shifted to the left in A2AKO hearts. L-NAME, a nonspecific NO synthase inhibitor, did not affect baseline coronary flow (CF) until the concentration reached 10 µM in A 2A WT (76.32 ± 11.35% from baseline, n=5). In A 2A KO, the CF decreased significantly by L-NAME only at a higher concentration (100 µM, 93.32 ± 5.8% from baseline, n=5). L-NMA (1 µM, n=4), another non-specific NO synthase inhibitor, also demonstrated similar results in decreasing CF (59.66±3.23% from baseline in A2AWT, while 81.76±8.91% in A2AKO). It was further demonstrated that the increase in CF by 100 µM NECA was significantly blunted with 10 µM L-NAME (377.08 ± 25.23% to 305.41 ± 30.73%, n=9) in A 2A WT but not in A 2A KO (153.66 ± 22.7% to 143.88 ± 36.65%, n=5). Similar results were also found using 50 nM of CGS-21680 instead of NECA in A 2A WT (346±22.85 to 277±31.39, n=6). No change in CF to CGS-21680 was noted in A 2A AKO. Our data demonstrate, for the first time, that coronary A 2B AR was up-regulated in mice deficient in A 2A AR. We also provide direct evidence supporting a role for NO in A 2A AR-mediated coronary vasodilation. The data further support the role for A 2A AR in the regulation of basal coronary tone through the release of NO.

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“…It has been shown that b 2 -adrenoceptors, which are the main b-adrenoceptor subtype responsible for the vasodilator response induced by nonspecific b-agonists (O' Donnell & Wanstall, 1984), are less susceptible than b 1 -adrenoceptors to downregulation (Cohen & Schenck, 1987). In addition, b 3 -adrenoceptors can be upregulated when b 1 -and b 2 -adrenoceptor subtypes are downregulated (Rohrer et al, 1999;Moniotte et al, 2001). Moreover, it is known that high doses of ISO and other catecholamines can induce toxic effects (Balta et al, 1995;Banerjee et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation

Davel¹,

Kawamoto²,

Scavone³

et al. 2006

British J Pharmacology

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1 The aim of this study was to assess the effects of treatment with isoproterenol (ISO, 0.3 mg kg À1 day À1 , s.c.) for 7 days on the vascular reactivity of rat-isolated aortic rings. Additionally, potential mechanisms underlying the changes that involved the endothelial modulation of contractility were investigated. 2 Treatment with ISO induced cardiac hypertrophy without changes in haemodynamic parameters. Aortic rings from ISO-treated rats showed an increase in the contraction response to phenylephrine (PHE) and serotonin, but did not change relaxations produced by acetylcholine or isoproterenol. Removal of the endothelium increased the responses to PHE in both groups. However, this procedure was less effective in ISO-treated as compared with control rats. Endothelial cell removal abolished the increase in the response to PHE in ISO-treated rats. The presence of N o -nitro-L-arginine methyl ester shifted the concentration-response curve to PHE to the left in both groups of rats. However, this effect was more pronounced in the ISO group. In addition, aminoguanidine (50 mM) potentiated the actions of PHE only in the ISO group. ISO treatment increased nitric oxide synthase (NOS) activity and neuronal NOS and endothelial NOS protein expression in the aorta. 3 Neither losartan (10 mM) nor indomethacin (10 mM) abolished the effects of ISO on the actions of PHE. Superoxide dismutase (SOD, 150 U ml À1 ) and L-arginine (5 mM), but neither catalase (300 U ml À1 ) nor apocynin (100 mM), blocked the effect of ISO treatment. In addition, we observed an increase in superoxide anion levels as measured by ethidium bromide fluorescence and of copper and zinc superoxide dismutase protein expression in ISO-treated rats. 4 In conclusion, our data suggest that ISO treatment alters the endothelial cell-mediated modulation of the contraction to PHE in rat aorta. The increased maximal response of PHE seems to be due to an increase in superoxide anion generation, which inactivates some of the basal NO produced and counteracts NO-mediated negative modulation even in the presence of high NO production and antioxidant defence.

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Cardiovascular and Metabolic Alterations in Mice Lacking Both β1- and β2-Adrenergic Receptors

Cited by 257 publications

References 43 publications

Deletion of β-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation

Deletion of β-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation

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