Modulation of Adrenal Catecholamine Secretion by In Vivo Gene Transfer and Manipulation of G Protein–coupled Receptor Kinase-2 Activity

Lymperopoulos, Anastasios; Rengo, Giuseppe; Zincarelli, Carmela; Soltys, Stephen M.; Koch, Walter J.

doi:10.1038/sj.mt.6300371

Cited by 78 publications

(71 citation statements)

References 22 publications

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“…The hypothesis that GRK2 modulates chromaffin catecholamine secretion was further supported by experiments with adenoviral-mediated overexpression of GRK2 in rats as this caused an increase of plasma catecholamine levels. 31 Thus, elevated GRK2 expression levels and activity in the adrenal medulla appear to contribute greatly to plasma catecholamine elevation in HF, which certainly perpetuates the vicious SNS overdrive cycle in HF. 3,32 PHARMACOLOGICAL VERSUS GENE THERAPY STRATEGIES TARGETING ADRENERGIC SIGNALING IN HF Ideally, HF therapy would be designed to tackle the root of the underlying molecular signaling alterations and aimed at halting or reversing disease progression.…”

Section: Grk2: a Nodal Culprit In Hf Grk2 And The Cardiomyocytementioning

confidence: 99%

“…Most studies-including studies with bARKct expression in HF pigs-have shown a reversal of bAR dysfunction including receptor upregulation and a normalization of signaling; however, no doubt, there are effects of the bARKct that go beyond resensitization of cardiac bARs and these effects are currently being explored by us and others. 54,55 Adrenal GRK2 as a novel HF gene therapy target As discussed above, HF is associated with enhanced catecholamine secretion from the adrenal glands because of a 2c AR desensitization by GRK2. This central role in the critical elevation of plasma catecholamine levels contributing to HF development and progression renders adrenal GRK2 an interesting target for HF treatment.…”

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 99%

“…20 Methods to direct viruses to the adrenal medulla have also been developed to attempt bARKct-mediated gene therapy in the adrenal gland to inhibit GRK2-mediated a 2c AR desensitization. 55 Importantly, in an initial study directed toward a true gene therapeutic approach, adenoviral-mediated bARKct gene transfer to the adrenal gland of a genetic line of HF mice returned increased catecholamine release back to normal levels, which was accompanied by improved cardiac performance and bAR signaling. 19 Moreover, a rat MI model with adenovirus-mediated expression of bARKct in the adrenal medulla showed decreased plasma catecholamine levels positively influencing hemodynamic parameters and ejection fraction.…”

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 99%

“…Targeting GRK2 by gene therapy for HF J Reinkober et al also a natural consequence of clinical bAR blocker use, 55 and this is also seen with bARKct expression. Furthermore, in studies with bARKct in rat and pig models of HF, 40,46 chronic bARKct expression in failing myocardium resulted in lower circulating catecholamine levels, showing that when bARs are normalized there is feedback to the SNS to lower its stimulation.…”

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 99%

“…In addition, Völkers et al 54 recently demonstrated that a part of the positive inotropic effects of bARKct is attributable to the disruption of G bg -mediated inhibition of cardiac L-type Ca 2+ channels, as bARKct expression in myocytes significantly improved Ca 2+ cycling via augmentation of the L-type Ca 2+ channel current. Another bAR-independent effect of the bARKct in the heart appears to be reversal of GRK2-mediated insulin resistance in myocytes, 55 which definitely needs to be explored as contributing to the therapeutic effects of GRK2 inhibition in HF. Overall, these effects of bARKct expression need to be further explored to understand the apparent synergy between GRK2 inhibition and bAR blockade in HF in order to delineate future clinical applications.…”

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 99%

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Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

et al. 2012

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Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symptom oriented and do not currently address specific intracellular molecular signaling abnormalities. Therefore, new and innovative therapeutic approaches are warranted and, ideally, these could at least complement established therapeutic options if not replace them. Gene therapy has potential to serve in this regard in HF as vectors can be directed toward diseased myocytes and directly target intracellular signaling abnormalities. Within this review, we will dissect the adrenergic system contributing to HF development and progression with special emphasis on G-protein-coupled receptor kinase 2 (GRK2). The levels and activity of GRK2 are increased in HF and we and others have demonstrated that this kinase is a major molecular culprit in HF. We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of b-adrenergic receptor antagonism.

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Section: Grk2: a Nodal Culprit In Hf Grk2 And The Cardiomyocytementioning

confidence: 99%

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 99%

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 99%

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 99%

Section: Targeting Grk2 By Gene Therapy For Hf J Reinkober Et Almentioning

confidence: 99%

See 3 more Smart Citations

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

et al. 2012

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Cell Networks in Endocrine/Neuroendocrine Gland Function

Guérineau

Campos

Tissier

et al. 2022

Comprehensive Physiology

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Reproduction, growth, stress and metabolism are determined by endocrine/neuroendocrine systems that regulate circulating hormone concentrations. All these systems generate rhythms and changes in hormone pulsatility observed in a variety of pathophysiological states. Thus, the output of endocrine/neuroendocrine systems must be regulated within a narrow window of effective hormone concentrations but must also maintain a capacity for plasticity to respond to changing physiological demands. Remarkably most endocrinologists still have a 'textbook' view of endocrine gland organization which has emanated from 20 th century histological studies on thin 2D tissue sections. However, 21 st century technological advances, including indepth 3D imaging of specific cell types have vastly changed our knowledge. We now know that various levels of multi-cellular organization can be found across different glands, that organizational motifs can vary between species and can be modified to enhance or decrease hormonal release. This review focuses on how the organization of cells regulates hormone output using three endocrine/neuroendocrine glands that present different levels of organization and complexity: the adrenal medulla, with a single neuroendocrine cell type; the anterior pituitary, with multiple intermingled cell types; and the pancreas with multiple intermingled cell types organized into distinct functional units. We give an overview of recent methodologies that allow the study of the different components within endocrine systems, and particularly their temporal and spatial relationships. We believe the emerging findings about network organization, and its impact on hormone secretion, are crucial to understanding how homeostatic regulation of endocrine axes is carried out within endocrine organs themselves.

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Structure–activity relationship study of angiotensin II analogs in terms of β‐arrestin‐dependent signaling to aldosterone production

Valero

Sturchler²,

Jafferjee

et al. 2016

Pharmacology Res & Perspec

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The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion induction, a steroid hormone that contributes to the pathology of postmyocardial infarction (MI) heart failure (HF), is mediated by both Gq/11 proteins and β‐arrestins, both of which couple to the AngII type 1 receptors (AT1Rs) of adrenocortical zona glomerulosa (AZG) cells. Over the past several years, AngII analogs with increased selectivity (“bias”) toward β‐arrestin‐dependent signaling at the AT1R have been designed and described, starting with SII, the gold‐standard β‐arrestin‐”biased” AngII analog. In this study, we examined the relative potencies of an extensive series of AngII peptide analogs at relative activation of G proteins versus β‐arrestins by the AT1R. The major structural difference of these peptides from SII was their varied substitutions at position 5, rather than position 4 of native AngII. Three of them were found biased for β‐arrestin activation and extremely potent at stimulating aldosterone secretion in AZG cells in vitro, much more potent than SII in that regard. Finally, the most potent of these three ([Sar1, Cys(Et)5, Leu8]‐AngII, CORET) was further examined in post‐MI rats progressing to HF and overexpressing adrenal β‐arrestin1 in vivo. Consistent with the in vitro studies, CORET was found to exacerbate the post‐MI hyperaldosteronism, and, consequently, cardiac function of the post‐MI animals in vivo. Finally, our data suggest that increasing the size of position 5 of the AngII peptide sequence results in directly proportional increases in AT1R‐dependent β‐arrestin activation. These findings provide important insights for AT1R pharmacology and future AngII‐targeted drug development.

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Modulation of Adrenal Catecholamine Secretion by In Vivo Gene Transfer and Manipulation of G Protein–coupled Receptor Kinase-2 Activity

Cited by 78 publications

References 22 publications

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

Cell Networks in Endocrine/Neuroendocrine Gland Function

Structure–activity relationship study of angiotensin II analogs in terms of β‐arrestin‐dependent signaling to aldosterone production

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