Lymphocyte Levels of GRK2 (βARK1) Mirror Changes in the LVAD-Supported Failing Human Heart: Lower GRK2 Associated With Improved β-Adrenergic Signaling After Mechanical Unloading

Hata, Jonathan A.; Williams, Matthew Leighton; Schroder, Jacob N.; Lima, Brian; Keys, Janelle R.; Blaxall, Burns C.; Petrofski, Jason A.; Jakoi, Andre; Milano, Carmelo A.; Koch, Walter J.

doi:10.1016/j.cardfail.2006.02.011

Cited by 80 publications

(73 citation statements)

References 42 publications

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“…The reduction in ␤ARK1-associated PI3K activity could be due to lower PI3K␥ activity or reduced levels of ␤ARK1. Dynamic regulation of ␤ARK1 protein levels before and after LVAD is consistent with previous studies 18, 29 and may be one of the key components in the formation of the ␤ARK1/PI3K complex and initiation of deleterious signaling.…”

Section: Discussionsupporting

confidence: 90%

“…This approach is critically different from the strategy of using the inhibitor of ␤ARK1, ␤ARKct (the carboxyl-terminus of ␤ARK1), which has been shown to ameliorate contractility of failing human cardiomyocytes. 18,29 ␤ARKct sequesters G␤␥-subunits, which leads to inhibition of receptor phosphorylation by ␤ARK1, and this results in the amelioration of cardiac function. 18 The activation and subsequent reversal of ␤ARK1-associated PI3K activity after mechanical unloading reflects the fact that ␤ARK1-associated PI3K activity is part of the deleterious signal activated in conditions of heart failure that is reversed as part of the beneficial remodeling that occurs after LVAD support.…”

Section: Discussionmentioning

confidence: 99%

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Dynamic Regulation of Phosphoinositide 3-Kinase-γ Activity and β-Adrenergic Receptor Trafficking in End-Stage Human Heart Failure

et al. 2007

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Background-Downregulation of ␤-adrenergic receptors (␤ARs) under conditions of heart failure requires receptor targeting of phosphoinositide 3-kinase (PI3K)-␥ and redistribution of ␤ARs into endosomal compartments. Because support with a left ventricular assist device (LVAD) results in significant improvement of cardiac function in humans, we investigated the effects of mechanical unloading on regulation of PI3K␥ activity and intracellular distribution of ␤ARs. Additionally, we tested whether displacement of PI3K␥ from activated ␤ARs would restore agonist responsiveness in failing human cardiomyocytes. Methods and Results-To test the role of PI3K on ␤AR endocytosis in failing human hearts, we assayed for PI3K activity in human left ventricular samples before and after mechanical unloading (LVAD). Before LVAD, failing human hearts displayed a marked increase in ␤AR kinase 1 (␤ARK1)-associated PI3K activity that was attributed exclusively to enhanced activity of the PI3K␥ isoform. Increased ␤ARK1-coupled PI3K activity in the failing hearts was associated with downregulation of ␤ARs from the plasma membrane and enhanced sequestration into early and late endosomes compared with unmatched nonfailing controls. Importantly, LVAD support reversed PI3K␥ activation, normalized the levels of agonist-responsive ␤ARs at the plasma membrane, and depleted the ␤ARs from the endosomal compartments without changing the total number of receptors (sum of plasma membrane and early and late endosome receptors). To test whether the competitive displacement of PI3K from the ␤AR complex restored receptor responsiveness, we overexpressed the phosphoinositide kinase domain of PI3K (which disrupts ␤ARK1/PI3K interaction) in primary cultures of failing human cardiomyocytes. Adenoviral-mediated phosphoinositide kinase overexpression significantly increased basal contractility and rapidly reconstituted responsiveness to ␤-agonist. Conclusions-These results suggest a novel paradigm in which human ␤ARs undergo a process of intracellular sequestration that is dynamically reversed after LVAD support. Importantly, mechanical unloading leads to complete reversal in PI3K␥ and ␤ARK1-associated PI3K activation. Furthermore, displacement of active PI3K from ␤ARK1 restores ␤AR responsiveness in failing myocytes.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Dynamic Regulation of Phosphoinositide 3-Kinase-γ Activity and β-Adrenergic Receptor Trafficking in End-Stage Human Heart Failure

et al. 2007

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“…A decreased β-AR function has been reported in heart failure, which may also be associated with SAN dysfunction (28). In this case, SAN failure occurs via a decreased β-AR expression, together with an increase in GRK activity in the heart and mirrored in some cases, in peripheral blood mononuclear cells (28)(29)(30)(31), both in humans (28,29,(32)(33)(34)(35) and in experimental models (34)(35)(36)(37)(38). A decreased expression and an increased desensitization of β-AR directly led to a loss of β-adrenergic function in the failing heart (28).…”

Section: R420qmentioning

confidence: 91%

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

Wang¹,

Mesirca²,

Marqués-Sulé³

et al. 2017

JCI Insight

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“…Overall, our data put forward GRK2 as a new molecular link among aging, insulin resistance/obesity and cardiovascular co-morbidities. Since circulating GRK2 levels have been shown to mirror cardiac expression [18] and increased levels of this protein are found in peripheral blood cells from metabolic syndrome patients [11] and from heart failure patients [19][20] , in particular in those with diabetes mellitus [21] , it will be interesting to explore the potential use of GRK2 as a prognostic cardiovascular risk marker when co-morbidities such as diabetes, insulin resistance and obesity are present.…”

Section: Research Highlightmentioning

confidence: 99%

Linking Cardiac Insulin Resistance and Heart Failure: Grk2 as an Integrative Node

Lucas

Jurado-Pueyo

Vila-Bedmar

et al. 2015

Cardiovasc Regen Med

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G protein-coupled receptor kinase 2 (GRK2) has arisen as a signaling hub with critical regulatory roles in cardiac function and dysfunction. Cardiac GRK2 levels are elevated during hypertension, cardiac ischemia and heart failure both in humans and in experimental models, while genetic inhibition of GRK2 results cardioprotective in different animal models of these conditions. However, the mechanistic grounds underlying these effects are not completely understood. Recent research has indicated that GRK2 not only phosphorylates and desensitizes G protein-coupled receptors (GPCR) that are important for heart function such as β-adrenergic or angiotensin type 1, but also modulates other pathways relevant for cardiac physiology such as the insulin signaling cascade. Using GRK2 hemizygous (GRK2+/-) mice, we have unveiled that a lower GRK2 dosage promotes enhanced insulin sensitivity in adult murine hearts what correlates with a cardioprotective gene expression profile. Also, GRK2 levels increase in cardiac tissue in well-established experimental models of systemic insulin resistance, such as high fat diet (HFD) feeding or ob/ob mice what parallels the impaired cardiac insulin sensitivity observed in these conditions. Our findings suggest that pathological inputs of different etiology such as increased catecholamine levels or high dietary fat converge in common important nodes key to the progress of the pathology. One such key connecting hub is GRK2, whose enhanced cardiac expression could promote progression towards maladaptive myocardial remodeling and heart failure.To cite this article: Elisa Lucas, et al. Linking cardiac insulin resistance and heart failure: GRK2 as an integrative node.

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Lymphocyte Levels of GRK2 (βARK1) Mirror Changes in the LVAD-Supported Failing Human Heart: Lower GRK2 Associated With Improved β-Adrenergic Signaling After Mechanical Unloading

Cited by 80 publications

References 42 publications

Dynamic Regulation of Phosphoinositide 3-Kinase-γ Activity and β-Adrenergic Receptor Trafficking in End-Stage Human Heart Failure

Dynamic Regulation of Phosphoinositide 3-Kinase-γ Activity and β-Adrenergic Receptor Trafficking in End-Stage Human Heart Failure

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

Linking Cardiac Insulin Resistance and Heart Failure: Grk2 as an Integrative Node

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