Reversal of impaired myocardial β-adrenergic receptor signaling by continuous-flow left ventricular assist device support

Akhter, Shahab A.; D’Souza, Kenneth; Malhotra, Ricky; Staron, Michelle L.; Valeroso, Tracy B.; Fedson, Savitri; Anderson, Allen S.; Raman, Jai; Jeevanandam, Valluvan

doi:10.1016/j.healun.2010.01.010

Cited by 32 publications

(30 citation statements)

References 28 publications

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“…Enhanced GRK2 expression and activity are also linked to hypertension 75 , cardiac hypertrophy 76 , and MI 65 . Perhaps most intriguingly, GRK2 levels often increase prior to overt clinical HF 66, 71 , and normalize in concert with improved β-AR signaling and ventricular function 77, 78 , as seen in patients using left ventricular assist devices (LVADs) 79–81 . Such findings have been interpreted to cast GRK2 as an alluring therapeutic target and potential biomarker of cardiac function 77 .…”

Section: Grks In Cardiac Pathologiesmentioning

confidence: 99%

G Protein Coupled Receptor Kinases as Therapeutic Targets in Cardiovascular Disease

Belmonte

Blaxall

2011

Circulation Research

104

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G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are responsible for regulating a wide variety of physiological processes. This is accomplished via ligand binding to GPCRs, activating associated heterotrimeric G proteins and intracellular signaling pathways. G protein-coupled receptor kinases (GRKs), in concert with β-arrestins, classically desensitize receptor signal transduction, thus preventing hyperactivation of GPCR second messenger cascades. As changes in GRK expression have featured prominently in many cardiovascular pathologies, including heart failure, myocardial infarction, hypertension, and cardiac hypertrophy, GRKs have been intensively studied as potential diagnostic or therapeutic targets. Herein, we review our evolving understanding of the role of GRKs in cardiovascular pathophysiology.

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Section: Grks In Cardiac Pathologiesmentioning

confidence: 99%

G Protein Coupled Receptor Kinases as Therapeutic Targets in Cardiovascular Disease

Belmonte

Blaxall

2011

Circulation Research

104

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“…Based on a study showing enhanced functional recovery of a failing heart by concomitant unloading and adenoviral-mediated β 2 -AR overexpression, a possible role for βARKct treatment in the unloaded heart was proposed. Unloading via a left ventricular assist device (LVAD) leads to reversal of pathological β-AR downregulation and desensitization [28][29][30]. Previously increased GRK2 levels and activity are also reduced in the myocardium as well as circulating lymphocytes [31].…”

Section: Myocardical Injury Is Limited By βArkctmentioning

confidence: 99%

βARKct: A Therapeutic Approach for Improved Adrenergic Signaling and Function in Heart Disease

Brinks

Koch

2010

J. of Cardiovasc. Trans. Res.

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One of the most powerful regulators of cardiovascular function is catecholamine-stimulated adrenergic receptor (AR) signaling. The failing heart is characterized by desensitization and impaired beta-AR responsiveness as a result of upregulated G protein-coupled receptor kinase-2 (GRK2) present in injured myocardium. Deterioration of cardiac function is progressively enhanced by chronic adrenergic over-stimulation due to increased levels of circulating catecholamines. Increased GRK2 activity contributes to this pathological cycle of over-stimulation but lowered responsiveness. Over the past two decades the GRK2 inhibitory peptide betaARKct has been identified as a potential therapy that is able to break this vicious cycle of self-perpetuating deregulation of the beta-AR system and subsequent myocardial malfunction, thus halting development of cardiac failure. The betaARKct has been shown to interfere with GRK2 binding to the betagamma subunits of the heterotrimeric G protein, therefore inhibiting its recruitment to the plasma membrane that normally leads to phosphorylation and internalization of the receptor. In this article we summarize the current data on the therapeutic effects of betaARKct in cardiovascular disease and report on recent and ongoing studies that may pave the way for this peptide towards therapeutic application in heart failure and other states of cardiovascular disease.

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“…In fact, human studies have shown that GRK2 up-regulation in failing myocardium may have novel diagnostic and prognostic value as its levels in the heart are mirrored by levels in white blood cells and so it can be measured peripherally 10-15 . Levels in failing myocardium correlate with cardiac dysfunction and improved cardiac function in HF is associated with lower GRK2 levels 11,13,14,16 . These aspects of human heart disease are also mirrored in animal models of HF, where GRK2 levels are increased early in pathological cardiac hypertrophy and myocardial ischemia, which appears instrumental in HF development 17 .…”

Section: Introductionmentioning

confidence: 99%

G Protein–Coupled Receptor Kinase 2

Woodall

Ciccarelli

Woodall³

et al. 2014

Circulation Research

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Heart failure (HF) causes a tremendous burden on the worldwide healthcare system, affecting more than 23 million people. There are many cardiovascular disorders that contribute to the development of HF and multiple risk factors that accelerate its occurrence, but regardless of its underlying cause, HF is characterized by a marked decrease in myocardial contractility and loss of pump function. One biomarker molecule consistently shown to be upregulated in human HF and several animal models is G protein-coupled receptor (GPCR) kinase 2 (GRK2), a kinase originally discovered to be involved in GPCR desensitization, especially β-adrenergic receptors (βARs). Indeed, higher levels of GRK2 can impair βAR-mediated inotropic reserve and its inhibition or molecular reduction has shown to improve pump function in several animal models including a pre-clinical pig model of HF. Recently, non-classical roles for GRK2 in cardiovascular disease have been described, including negative regulation of insulin signaling, a role in myocyte cell survival and apoptotic signaling, and it has been shown to be localized in/on mitochondria. These new roles of GRK2 suggest that GRK2 may be a nodal link in the myocyte, influencing both cardiac contractile function and cell metabolism and survival and contributing to HF independent of its canonical role on GPCR desensitization. In this review, classical and non-classical roles for GRK2 will be discussed, focusing on recently discovered roles for GRK2 in cardiomyocyte metabolism and the effects that these roles may have on myocardial contractile function and HF development.

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Reversal of impaired myocardial β-adrenergic receptor signaling by continuous-flow left ventricular assist device support

Abstract: Background-Myocardial β-adrenergic receptor (β-AR) signaling is severely impaired in chronic heart failure (HF). The objective of this study is to determine if LV β-AR signaling can be restored following continuous-flow LVAD support.

Cited by 32 publications

References 28 publications

G Protein Coupled Receptor Kinases as Therapeutic Targets in Cardiovascular Disease

G Protein Coupled Receptor Kinases as Therapeutic Targets in Cardiovascular Disease

βARKct: A Therapeutic Approach for Improved Adrenergic Signaling and Function in Heart Disease

G Protein–Coupled Receptor Kinase 2

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