ArticleJournal of the American College of Cardiology2014
Simultaneous adrenal and cardiac g-protein-coupled receptor-gβγ inhibition halts heart failure progression.
Article in Journal of the American College of Cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 52 citations in OpenAlex.
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- Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure.Acta physiologica (Oxford, England) · 2025Review
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- Adrenoceptor Desensitization: Current Understanding of Mechanisms.Pharmacological reviews · 2024Review
- Novel roles for G protein-coupled receptor kinases in cardiac injury and repair.Biochemical Society transactions · 2023Review
- GRK2 in cardiovascular disease and its potential as a therapeutic target.Journal of molecular and cellular cardiology · 2022Review
- G protein-coupled receptor signaling: transducers and effectors.American journal of physiology. Cell physiology · 2022Review
- Early Gβγ-GRK2 Inhibition Ameliorates Osteoarthritis Development by Simultaneous Anti-Inflammatory and Chondroprotective Effects.International journal of molecular sciences · 2022Article
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- Computational models of cardiac hypertrophy.Progress in biophysics and molecular biology · 2021Review
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- Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging.American journal of physiology. Heart and circulatory physiology · 2020Article
- G protein-coupled receptor kinases as therapeutic targets in the heart.Nature reviews. Cardiology · 2019Review
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8 authors at 2 institutions in 1 country.
Funding
Abstract
objectivesThe authors propose simultaneous inhibition of Gβγ signaling in the heart and the adrenal gland as a novel therapeutic approach for heart failure (HF).
backgroundElevated 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.
methodsWe investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, pressure-overload model of HF.
resultsDaily 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.
conclusionsThese 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.