G Protein–Coupled Receptor Kinase 2

Woodall, Meryl C.; Ciccarelli, Michele; Woodall, Benjamin P.; Koch, Walter J.

doi:10.1161/circresaha.114.300513

Cited by 78 publications

(48 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because GRK2 inhibition also mediated the down-regulation of FASN-dependent cardio-lipotoxicity, patients with high morbidity and multiple risk factors may benefit from GRK2 inhibition. The additional insulin sensitivityenhancing activity of GRK2 inhibition (13,58) may further increase the value of such a strategy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Alla

Graemer

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Impairment of myocardial fatty acid substrate metabolism is characteristic of late-stage heart failure and has limited treatment options. Here, we investigated whether inhibition of G-protein-coupled receptor kinase 2 (GRK2) could counteract the disturbed substrate metabolism of late-stage heart failure. The heart failure-like substrate metabolism was reproduced in a novel transgenic model of myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. The increased fatty acid utilization of FASN transgenic neonatal cardiomyocytes rapidly switched to a heart failure phenotype in an adult-like lipogenic milieu. Similarly, adult FASN transgenic mice developed signs of heart failure. The development of disturbed substrate utilization of FASN transgenic cardiomyocytes and signs of heart failure were retarded by the transgenic expression of GRKInh, a peptide inhibitor of GRK2. Cardioprotective GRK2 inhibition required an intact ERK axis, which blunted the induction of cardiotoxic transcripts, in part by enhanced serine 273 phosphorylation of Pparg (peroxisome proliferator-activated receptor ␥). Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure-promoting Pparg-regulated genes. Thus, GRK2 inhibition is a novel approach that targets the dysfunctional substrate metabolism of the failing heart.Heart failure is a debilitating syndrome that involves insufficient cardiac performance. Multiple pathomechanisms have been elucidated, but treatment options remain insufficient, and hence the mortality of heart failure is high (1). The causes of heart failure are complex with ischemic heart disease being the most frequently associated condition (2). Co-existing disorders such as diabetes, hypertension, and obesity further deteriorate symptoms (3). Despite having a different etiology, late-stage heart failure is commonly characterized by severe changes in myocardial substrate metabolism, with a switch from fatty acid oxidation toward predominant glycolysis (4 -6). Conflicting evidence exists as to whether this substrate switch is beneficial or detrimental (7), but several previous studies have indicated that an increased availability of lipid substrates that counteract the substrate switch could improve cardiac function (7,8). Moreover, treatment options, which improve substrate availability, are attractive because the failing heart is often considered to be "an engine running out of fuel" (9).Following this concept, we aimed to investigate the impact of improved cardiac substrate availability by generating transgenic mice with myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. Such an approach is also supported by data obtained for myocardium-specific Fasn deficiency, which have revealed the cardioprotective potential of Fasn (10). Moreover, hearts from patients with heart failure showed an increased express...

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Alla

Graemer

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…where m is muscle mass, Lo is muscle length, Lf/Lo is the ratio of fiber length to optimal muscle length, and density of muscle () ϭ 1.06 g/cm 3 . Lf/Lo was 0.45 for EDL and 0.69 for soleus.…”

Section: Methodsmentioning

confidence: 99%

“…Equally important to the stimulation and activation of GPCRs is the desensitization and "shutting-off" of the receptor. This task is primarily conducted by the GPCR kinase (GRK) family of proteins (2,3). GRK2 is ubiquitously expressed throughout the tissues of the body, perhaps most notably in the heart where its regulation of adrenergic receptors (ARs) is critical to physiological heart function.…”

mentioning

confidence: 99%

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy

Woodall

Luongo

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds progression to heart failure. Despite the importance of this kinase in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease. In this study we generated a novel skeletal muscle-specific GRK2 knock-out (KO) mouse (MLC-Cre:GRK2 fl/fl ) to gain a better understanding of the role of GRK2 in skeletal muscle physiology. In isolated muscle mechanics testing, GRK2 ablation caused a significant decrease in the specific force of contraction of the fast-twitch extensor digitorum longus muscle yet had no effect on the slow-twitch soleus muscle. Despite these effects in isolated muscle, exercise capacity was not altered in MLC-Cre:GRK2 fl/fl mice compared with wild-type controls. Skeletal muscle hypertrophy stimulated by clenbuterol, a ␤ 2 -adrenergic receptor (␤ 2 AR) agonist, was significantly enhanced in MLC-Cre:GRK2 fl/fl mice; mechanistically, this seems to be due to increased clenbuterol-stimulated pro-hypertrophic Akt signaling in the GRK2 KO skeletal muscle. In summary, our study provides the first insights into the role of GRK2 in skeletal muscle physiology and points to a role for GRK2 as a modulator of contractile properties in skeletal muscle as well as ␤ 2 AR-induced hypertrophy. G protein-coupled receptors (GPCRs)2 comprise the largest family of membrane proteins in the genome. GPCRs regulate diverse processes throughout the body by responding to a vast array of extracellular stimuli including hormones, neurotransmitters, and photons of light (1). Equally important to the stimulation and activation of GPCRs is the desensitization and "shutting-off" of the receptor. This task is primarily conducted by the GPCR kinase (GRK) family of proteins (2, 3). GRK2 is ubiquitously expressed throughout the tissues of the body, perhaps most notably in the heart where its regulation of adrenergic receptors (ARs) is critical to physiological heart function. Cardiac overexpression of GRK2 in mice suppresses contractility, whereas cardiac overexpression of the GRK2 inhibitor ␤ARKct (a C-terminal peptide that competes with GRK2 binding to G ␤␥ ) enhances contractile function (4). Catecholamine overdrive during heart failure drives increased GRK2 expression in the cardiomyocyte, ultimately leading to excessive desensitization of ␤ARs, loss of receptor density, and a drop in inotropic reserve (5-7). Indeed, myocardial inhibition or deletion of GRK2 can prevent and even reverse heart failure in numerous animal models (4, 8 -13).Although we have a firm understanding of the role of GRK2 in the physiology and pathophysiology of t...

show abstract

“…particular, this kinase has been recently identified as a negative modulator of insulin signals [5,8,9] . The insulin cascade is crucial to maintain cardiac functionality since the heart is an organ with a constitutive energy demand and, although fatty acids are the predominant substrate oxidized in the adult heart, the cardiac metabolic network is highly flexible and able to use other substrates when they are available, and this metabolic plasticity is key to normal cardiac physiology.…”

Section: Research Highlightmentioning

confidence: 99%

“…GRK2 has been suggested to play an important role in cardiac physiopathology, and its levels are increased in hypertension, cardiac ischemia, and in early stages of maladaptive myocardial remodeling and heart failure (reviewed in [2,3,4] ). On the other hand, genetic inhibition of this kinase has a cardioprotective effect in several animal models of cardiac dysfunction (reviewed in [5] ). However, the molecular mechanisms underlying both the deleterious and beneficial effects in cardiac function of the reported changes in GRK2 levels are not fully understood.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

G Protein–Coupled Receptor Kinase 2

Cited by 78 publications

References 65 publications

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy

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

Contact Info

Product

Resources

About