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Simultaneous adrenal and cardiac g-protein-coupled receptor-g?? inhibition halts heart failure progression.

ABSTRACT: The authors propose simultaneous inhibition of G?? signaling in the heart and the adrenal gland as a novel therapeutic approach for heart failure (HF).Elevated sympathetic nervous system activity is a salient characteristic of HF progression. It causes pathologic desensitization of ?-adrenergic receptors (?-AR), facilitated predominantly through G??-mediated signaling. The adrenal glands are key contributors to the chronically elevated plasma catecholamine levels observed in HF, where adrenal ?2-AR feedback inhibitory function is impaired also through G??-mediated signaling.We investigated the efficacy of a small molecule G?? inhibitor, gallein, in a clinically relevant, pressure-overload model of HF.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 ?-AR membrane density in cardiomyocytes, attenuated G??-mediated G-protein-coupled receptor kinase 2-phosphoinositide 3-kinase ? membrane recruitment, and reduced Akt (protein kinase B) and glycogen synthase kinase 3? phosphorylation. Gallein also reduced circulating plasma catecholamine levels and catecholamine production in isolated mouse adrenal glands by restoring adrenal ?2-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.These data suggest small molecule G?? inhibition as a systemic pharmacologic therapy for HF by simultaneously normalizing pathologic adrenergic/G?? signaling in both the heart and the adrenal gland. Our data also suggest important endocrine/cardiovascular interactions and a possible role for small molecule G?? inhibition in treating endocrine tumors such as pheochromocytoma, in addition to HF.

SUBMITTER: Kamal FA

PROVIDER: S-EPMC4083020 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Simultaneous adrenal and cardiac g-protein-coupled receptor-gβγ inhibition halts heart failure progression.

Kamal Fadia A FA Mickelsen Deanne M DM Wegman Katherine M KM Travers Joshua G JG Moalem Jacob J Hammes Stephen R SR Smrcka Alan V AV Blaxall Burns C BC

Journal of the American College of Cardiology 20140402 23

<h4>Objectives</h4>The authors propose simultaneous inhibition of Gβγ signaling in the heart and the adrenal gland as a novel therapeutic approach for heart failure (HF).<h4>Background</h4>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 l ...[more]

PMID: 24703913

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Project description:Aims Myocardial infarction (MI) is the most common cause of heart failure (HF) worldwide. G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy in animal models. However, the role of GRK5 in ischemic heart disease is still unknown. In this study, we evaluated whether myocardial GRK5 plays a critical role post-MI in mice and included the examination of specific cardiac immune and inflammatory responses.Methods and results Cardiomyocyte-specific GRK5 overexpressing transgenic mice (TgGRK5) and non-transgenic littermate control (NLC) mice as well as cardiomyocyte-specific GRK5 knockout mice (GRK5cKO) and wild type (WT) were subjected to MI and, functional as well as structural changes together with outcomes were studied. TgGRK5 post-MI mice showed decreased cardiac function, augmented left ventricular dimension and decreased survival rate compared to NLC post-MI mice. Cardiac hypertrophy and fibrosis as well as fetal gene expression were increased post-MI in TgGRK5 compared to NLC mice. In TgGRK5 mice, GRK5 elevation produced immuno-regulators that contributed to the elevated and long-lasting leukocyte recruitment into the injured heart and ultimately to chronic cardiac inflammation. We found an increased presence of pro-inflammatory neutrophils and macrophages as well as neutrophils, macrophages and T-lymphocytes at 4-days and 8-weeks respectively post-MI in TgGRK5 hearts. Conversely, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (predominantly monocytes) to the heart, improved contractility and reduced mortality compared to WT post-MI mice. Interestingly, cardiomyocyte-specific GRK2 transgenic mice did not share the same phenotype of TgGRK5 mice and did not have increased cardiac leukocyte migration and cytokine or chemokine production post-MI.Conclusions Our study shows that myocyte GRK5 has a crucial and GRK-selective role on the regulation of leucocyte infiltration into the heart, cardiac function and survival in a murine model of post-ischemic HF, supporting GRK5 inhibition as a therapeutic target for HF.

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Simultaneous adrenal and cardiac g-protein-coupled receptor-g?? inhibition halts heart failure progression.

Publications

Simultaneous adrenal and cardiac g-protein-coupled receptor-gβγ inhibition halts heart failure progression.

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