Simultaneous adrenal and cardiac g-protein-coupled receptor-gβγ inhibition halts heart failure progression
Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved..
OBJECTIVES: The authors propose simultaneous inhibition of Gβγ signaling in the heart and the adrenal gland as a novel therapeutic approach for heart failure (HF).
BACKGROUND: Elevated sympathetic nervous system activity is a salient characteristic of HF progression. It causes pathologic desensitization of β-adrenergic receptors (β-AR), facilitated predominantly through Gβγ-mediated signaling. The adrenal glands are key contributors to the chronically elevated plasma catecholamine levels observed in HF, where adrenal α2-AR feedback inhibitory function is impaired also through Gβγ-mediated signaling.
METHODS: We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, pressure-overload model of HF.
RESULTS: Daily gallein treatment (10 mg/kg/day), initiated 4 weeks after transverse aortic constriction, improved survival and cardiac function and attenuated cardiac remodeling. Mechanistically, gallein restored β-AR membrane density in cardiomyocytes, attenuated Gβγ-mediated G-protein-coupled receptor kinase 2-phosphoinositide 3-kinase γ membrane recruitment, and reduced Akt (protein kinase B) and glycogen synthase kinase 3β phosphorylation. Gallein also reduced circulating plasma catecholamine levels and catecholamine production in isolated mouse adrenal glands by restoring adrenal α2-AR feedback inhibition. In human adrenal endocrine tumors (pheochromocytoma), gallein attenuated catecholamine secretion, as well as G-protein-coupled receptor kinase 2 expression and membrane translocation.
CONCLUSIONS: These data suggest small molecule Gβγ inhibition as a systemic pharmacologic therapy for HF by simultaneously normalizing pathologic adrenergic/Gβγ signaling in both the heart and the adrenal gland. Our data also suggest important endocrine/cardiovascular interactions and a possible role for small molecule Gβγ inhibition in treating endocrine tumors such as pheochromocytoma, in addition to HF.
| Errataetall: |
CommentIn: J Am Coll Cardiol. 2014 Jun 17;63(23):2558-9. - PMID 24703911 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2014 |
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| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Journal of the American College of Cardiology - 63(2014), 23 vom: 17. Juni, Seite 2549-2557 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kamal, Fadia A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.08.2014 Date Revised 21.10.2021 published: Print-Electronic CommentIn: J Am Coll Cardiol. 2014 Jun 17;63(23):2558-9. - PMID 24703911 Citation Status MEDLINE |
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| doi: |
10.1016/j.jacc.2014.02.587 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM237094010 |
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| 100 | 1 | |a Kamal, Fadia A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Simultaneous adrenal and cardiac g-protein-coupled receptor-gβγ inhibition halts heart failure progression |
| 264 | 1 | |c 2014 | |
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| 500 | |a Date Completed 28.08.2014 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: J Am Coll Cardiol. 2014 Jun 17;63(23):2558-9. - PMID 24703911 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a OBJECTIVES: The authors propose simultaneous inhibition of Gβγ signaling in the heart and the adrenal gland as a novel therapeutic approach for heart failure (HF) | ||
| 520 | |a BACKGROUND: Elevated sympathetic nervous system activity is a salient characteristic of HF progression. It causes pathologic desensitization of β-adrenergic receptors (β-AR), facilitated predominantly through Gβγ-mediated signaling. The adrenal glands are key contributors to the chronically elevated plasma catecholamine levels observed in HF, where adrenal α2-AR feedback inhibitory function is impaired also through Gβγ-mediated signaling | ||
| 520 | |a METHODS: We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, pressure-overload model of HF | ||
| 520 | |a RESULTS: Daily gallein treatment (10 mg/kg/day), initiated 4 weeks after transverse aortic constriction, improved survival and cardiac function and attenuated cardiac remodeling. Mechanistically, gallein restored β-AR membrane density in cardiomyocytes, attenuated Gβγ-mediated G-protein-coupled receptor kinase 2-phosphoinositide 3-kinase γ membrane recruitment, and reduced Akt (protein kinase B) and glycogen synthase kinase 3β phosphorylation. Gallein also reduced circulating plasma catecholamine levels and catecholamine production in isolated mouse adrenal glands by restoring adrenal α2-AR feedback inhibition. In human adrenal endocrine tumors (pheochromocytoma), gallein attenuated catecholamine secretion, as well as G-protein-coupled receptor kinase 2 expression and membrane translocation | ||
| 520 | |a CONCLUSIONS: These data suggest small molecule Gβγ inhibition as a systemic pharmacologic therapy for HF by simultaneously normalizing pathologic adrenergic/Gβγ signaling in both the heart and the adrenal gland. Our data also suggest important endocrine/cardiovascular interactions and a possible role for small molecule Gβγ inhibition in treating endocrine tumors such as pheochromocytoma, in addition to HF | ||
| 650 | 4 | |a Comparative Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a catecholamines | |
| 650 | 4 | |a fibrosis | |
| 650 | 4 | |a heart failure | |
| 650 | 4 | |a hypertrophy | |
| 650 | 4 | |a sympathetic nervous system | |
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| 700 | 1 | |a Mickelsen, Deanne M |e verfasserin |4 aut | |
| 700 | 1 | |a Wegman, Katherine M |e verfasserin |4 aut | |
| 700 | 1 | |a Travers, Joshua G |e verfasserin |4 aut | |
| 700 | 1 | |a Moalem, Jacob |e verfasserin |4 aut | |
| 700 | 1 | |a Hammes, Stephen R |e verfasserin |4 aut | |
| 700 | 1 | |a Smrcka, Alan V |e verfasserin |4 aut | |
| 700 | 1 | |a Blaxall, Burns C |e verfasserin |4 aut | |
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