Cardiac and neuroprotection regulated by α<sub>1</sub>-adrenergic receptor subtypes

Perez, Dianne M.; Doze, Van A.

doi:10.3109/10799893.2010.550008

Cited by 55 publications

(60 citation statements)

References 185 publications

(183 reference statements)

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“…On the other hand, previous studies have suggested the CAM-α 1A AR mice are cardio-protected, which may contribute to its increased longevity (reviewed in Perez and Doze 2011). While CAM-α 1A AR mice also display cardiac hypertrophy as in CAM-α 1B AR mice, α 1A AR activation results in positive adaptation of the heart to protect against ischemic damage through preconditioning via cardiac protective IL-6 and JAK/STAT pathways or by preventing apoptosis due to increased glucose uptake (Rorabaugh et al 2005;Papay et al 2013, Perez, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, chronic activation of the α 1B AR increases depression-like behavior (Doze et al 2009). In transgenic models of increased α 1B AR activity, a maladaptive cardiac hypertrophy was either present at baseline or developed over time concomitantly with other cardiac and cardiacrelated deficits (reviewed in Perez and Doze 2011). Chronic α 1B AR activity also leads to age-related apoptotic neurodegeneration, a synucleinopathy with Parkinson-like movement deficits similar to human multiple system atrophy (Zuscik et al 2000;Papay et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

Collette

Amoth

et al. 2014

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The α 1 -adrenergic receptor (α 1 AR) subtypes, α 1A AR and α 1B AR, have differential effects in the heart and central nervous system. Long-term stimulation of the α 1A AR subtype prolongs lifespan and provides cardio-and neuro-protective effects. We examined the lifespan of constitutively active mutant (CAM)-α 1B AR mice and the incidence of cancer in mice expressing the CAM form of either the α 1A AR (CAM-α 1A AR mice) or α 1B AR. CAM-α 1B AR mice have a significantly shortened lifespan when compared with wild-type (WT) animals; however, the effect was sex dependent. Female CAM-α 1B AR mice lived significantly shorter lives, while the median lifespan of male CAM-α 1B AR mice was not different when compared with that of WT animals. There was no difference in the incidence of cancer in either sex of CAM-α 1B AR mice. The incidence of cancer was significantly decreased in CAM-α 1A AR mice when compared with that in WT, and no sex-dependent effects were observed. Further study is warranted on cancer incidence after activation of each α 1 AR subtype and the effect of sex on lifespan following activation of the α 1B AR. The implications of a decrease in cancer incidence following long-term α 1A AR stimulation could lead to improved treatments for cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

Collette

Amoth

et al. 2014

AGE

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“…However, several studies have demonstrated that chronic hypertrophy can be associated with a significant increase in the risk of heart failure, ischemic heart disease, and apoptosis [i.e., maladaptive hypertrophy; reviewed in Selvetella et al (2004)]. Several studies have suggested that activation of the a 1A -AR but not the a 1B -AR subtype can be cardioprotective, which indicates a different involvement of the a 1 -AR subtypes in the progression of adaptive to maladaptive hypertrophy [reviewed in Doze (2011) andJensen et al (2011)]. Because IL-6-mediated hypertrophy is also adaptive and cardioprotective (Kunisada et al, 2000;Jacoby et al, 2003;Hilfiker-Kleiner et al, 2004;Butler et al, 2006), our results suggest that IL-6 may be partially responsible for cardioprotection seen in the CAM a 1A -AR mouse.…”

Section: Discussionmentioning

confidence: 99%

α_1A-Adrenergic Receptors Regulate Cardiac Hypertrophy In Vivo Through Interleukin-6 Secretion

et al. 2013

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The role of a 1 -adrenergic receptors (ARs) in the regulation of cardiac hypertrophy is still unclear, because transgenic mice demonstrated hypertrophy or the lack of it despite high receptor overexpression. To further address the role of the a 1 -ARs in cardiac hypertrophy, we analyzed unique transgenic mice that overexpress constitutively active mutation (CAM) a 1A -ARs or CAM a 1B -ARs under the regulation of large fragments of their native promoters. These constitutively active receptors are expressed in all tissues that endogenously express their wild-type counterparts as opposed to only myocyte-targeted transgenic mice. In this study, we discovered that CAM a 1A -AR mice in vivo have cardiac hypertrophy independent of changes in blood pressure, corroborating earlier studies, but in contrast to myocytetargeted a 1A -AR mice. We also found cardiac hypertrophy in CAM a 1B -AR mice, in agreement with previous studies, but hypertrophy only developed in older mice. We also discovered unique a 1 -AR-mediated hypertrophic signaling that was AR subtypespecific with CAM a 1A -AR mice secreting atrial naturietic factor and interleukin-6 (IL-6), whereas CAM a 1B -AR mice expressed activated nuclear factor-kB (NF-kB). These particular hypertrophic signals were blocked when the other AR subtype was coactivated. We also discovered that crossbreeding the two CAM models (double CAM a 1A/B -AR) inhibited the development of hypertrophy and was reversible with single receptor activation, suggesting that coactivation of the receptors can lead to novel antagonistic signal transduction. This was confirmed by demonstrating antagonistic signals that were even lower than normal controls in the double CAM a 1A/B -AR mice for p38, NF-kB, and the IL-6/glycoprotein 130/signal transducer and activator of transcription 3 pathway. Because a 1A/B double knockout mice fail to develop hypertrophy in response to IL-6, our results suggest that IL-6 is a major mediator of a 1A -AR cardiac hypertrophy.

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“…It was recently shown that transgenic mice expressing a constitutively active mutant of the a1A, but not of the a1B-AR, have an increased life span, mainly as a result of cardiac and neuroprotection (Perez and Doze, 2011), broadening the potential therapeutic applications of drugs that selectively interfere with the signaling that results from activation of each of these a1-AR subtypes. To accomplish this, an understanding of the signaling profiles of a1-AR ligands in native and recombinant receptor systems is important.…”

Section: Confocal Microscopy and [mentioning

confidence: 99%

Differential Phosphorylation, Desensitization, and Internalization ofα1A−Adrenoceptors Activated by Norepinephrine and Oxymetazoline

et al. 2013

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Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an a1-adrenoceptor (AR) agonist of the imidazoline class. One cause of tachyphylaxis is receptor desensitization, usually accompanied by phosphorylation and internalization. It is well established that a1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the a1B and a1D subtypes. However, here we show in human embryonic kidney-293 cells that the low-efficacy agonist OXY induces G protein-coupled receptor kinase 2-dependent a1A-AR phosphorylation, followed by rapid desensitization and internalization (∼40% internalization after 5 minutes of stimulation), whereas phosphorylation of a1A-ARs exposed to NE depends to a large extent on protein kinase C activity and is not followed by desensitization, and the receptors undergo delayed internalization (∼35% after 60 minutes of stimulation). Native a1A-ARs from rat tail artery and vas deferens are also desensitized by OXY, but not by NE or PE, indicating that this property of OXY is not limited to recombinant receptors expressed in cell systems. The results of the present study are clearly indicative of agonist-directed a1A-AR regulation. OXY shows functional selectivity relative to NE and PE at a1A-ARs, leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biologic process regulated by a1A-ARs.

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Cardiac and neuroprotection regulated by α₁-adrenergic receptor subtypes

Cited by 55 publications

References 185 publications

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

α_1A-Adrenergic Receptors Regulate Cardiac Hypertrophy In Vivo Through Interleukin-6 Secretion

Differential Phosphorylation, Desensitization, and Internalization ofα1A−Adrenoceptors Activated by Norepinephrine and Oxymetazoline

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Cardiac and neuroprotection regulated by α1-adrenergic receptor subtypes

Cited by 55 publications

References 185 publications

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

α1A-Adrenergic Receptors Regulate Cardiac Hypertrophy In Vivo Through Interleukin-6 Secretion

Differential Phosphorylation, Desensitization, and Internalization ofα1A−Adrenoceptors Activated by Norepinephrine and Oxymetazoline

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Product

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Cardiac and neuroprotection regulated by α₁-adrenergic receptor subtypes

α_1A-Adrenergic Receptors Regulate Cardiac Hypertrophy In Vivo Through Interleukin-6 Secretion