Endothelial G Protein–Coupled Receptor Kinase 2 Regulates Vascular Homeostasis Through the Control of Free Radical Oxygen Species

Ciccarelli, Michele; Sorriento, Daniela; Franco, Antonietta; Fusco, Anna; Giudice, Carmine Del; Annunziata, Roberto; Cipolletta, Ersilia; Monti, Maria Gaia; Dorn, Gerald W.; Trimarco, Bruno; Iaccarino, Guido

doi:10.1161/atvbaha.113.302262

Cited by 32 publications

(27 citation statements)

References 39 publications

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“…This developmental importance of GRK2 may extend to the endothelium: deleting GRK2 in endothelial cells using a Tie-2-Cre mouse resulted in some abnormalities and changes in vasculogenesis as GRK2 is deleted prenatally in this murine model 26,27 . Interestingly, the increased inflammatory and oxidative stress seen in the endothelium of Tie-2-GRK2 KO mice is in contrast to vascular results found in heterozygous global GRK2 KO mice with similar decreases in GRK2 expression in endothelium, as these mice have improved endothelium function and also prevent the oxidative stress and dysfunction caused by angiotensin II (AngII) treatment 28 .…”

Section: Introductionmentioning

confidence: 92%

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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Section: Introductionmentioning

confidence: 92%

G Protein–Coupled Receptor Kinase 2

Woodall

Ciccarelli

Woodall³

et al. 2014

Circulation Research

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“…These data coupled with vascular smooth muscle targeting support GRK2 inhibition, not only in heart failure, but for hypertension as well. However, it must be noted that GRK2 has also been shown to be important in regulating endothelial inflammation and oxidative stress (51,239). For example, lower GRK2 exclusively in murine endothelial cells was recently shown to be associated with increased reactive oxygen species (51).…”

Section: Grk2 and Hypertensionmentioning

confidence: 99%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

126

152

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G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.

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“…In particular, several stressors increase the levels of GRK2 in mitochondria, in an ERK- and HSP90-dependent mechanism (73). The effects of such accumulation are still the object of investigation since opposite results in the literature show either a protective mechanism (28, 29, 74) or the acceleration of unfavorable processes (73). Nevertheless, given the established notion that the accumulation of GRK2 in plasma membrane inhibits GPCR signaling or its binding with cytosolic substrates activates pro-death signaling, the possibility to modulate GRK2 accumulation within specific organelles might in the future pose the strategy to regulate kinase effects in pathological conditions (Figure 4).…”

Section: Suggestions For Future Directionsmentioning

confidence: 99%

“Freeze, Don’t Move”: How to Arrest a Suspect in Heart Failure – A Review on Available GRK2 Inhibitors

Sorriento

Ciccarelli

Cipolletta

et al. 2016

Front. Cardiovasc. Med.

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Cardiovascular disease and heart failure (HF) still collect the largest toll of death in western societies and all over the world. A growing number of molecular mechanisms represent possible targets for new therapeutic strategies, which can counteract the metabolic and structural changes observed in the failing heart. G protein-coupled receptor kinase 2 (GRK2) is one of such targets for which experimental and clinical evidence are established. Indeed, several strategies have been carried out in place to interface with the known GRK2 mechanisms of action in the failing heart. This review deals with results from basic and preclinical studies. It shows different strategies to inhibit GRK2 in HF in vivo (βARK-ct gene therapy, treatment with gallein, and treatment with paroxetine) and in vitro (RNA aptamer, RKIP, and peptide-based inhibitors). These strategies are based either on the inhibition of the catalytic activity of the kinase (“Freeze!”) or the prevention of its shuttling within the cell (“Don’t Move!”). Here, we review the peculiarity of each strategy with regard to the ability to interact with the multiple tasks of GRK2 and the perspective development of eventual clinical use.

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Endothelial G Protein–Coupled Receptor Kinase 2 Regulates Vascular Homeostasis Through the Control of Free Radical Oxygen Species

Cited by 32 publications

References 39 publications

G Protein–Coupled Receptor Kinase 2

G Protein–Coupled Receptor Kinase 2

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

“Freeze, Don’t Move”: How to Arrest a Suspect in Heart Failure – A Review on Available GRK2 Inhibitors

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