G Protein–Coupled Receptor Kinase 2 Activity Impairs Cardiac Glucose Uptake and Promotes Insulin Resistance After Myocardial Ischemia

Abstract

Background Alterations in cardiac energy metabolism downstream of neurohormonal stimulation play a crucial role in the pathogenesis of heart failure (HF). The chronic adrenergic stimulation that accompanies HF is a signaling abnormality that leads to the up-regulation of G protein-coupled receptor kinase 2 (GRK2), which is pathological in the myocyte during disease progression in part due to uncoupling of the β-adrenergic receptor (βAR) system. In this study we explored the possibility that enhanced GRK2 expression and activity, as seen during HF, can negatively affect cardiac metabolism as part of its pathogenic profile. Methods and Results Positron Emission Tomography (PET) studies revealed that transgenic mice with cardiac-specific overexpression of GRK2 negatively impacted cardiac metabolism by inhibiting glucose uptake and desensitization of insulin signaling, which increases after ischemic injury and precedes HF development. Mechanistically, GRK2 interacts with and directly phosphorylates insulin receptor substrate-1 (IRS1) in cardiomyocytes causing insulin-dependent negative signaling feedback including inhibition of membrane translocation of the glucose transporter, GLUT4. This identifies IRS1 as a novel non-receptor target for GRK2 and represents a new pathological mechanism for this kinase in the failing heart. Importantly, inhibition of GRK2 activity prevents post-ischemic defects in myocardial insulin signaling and improves cardiac metabolism via normalized glucose uptake, which appears to participate in GRK2-targeted prevention of HF. Conclusions Our data provide novel insight into how GRK2 is pathological in the injured heart. Moreover, it appears to be a critical mechanistic link within neurohormonal crosstalk governing cardiac contractile signaling/function through βARs and metabolism through the insulin receptor.

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

“…This is consistent with the notion of GRK2 is a relevant negative modulator of insulin signaling in heart as so happens in other key insulin target tissues [8,9] . Moreover, in addition to the previously reported up-regulation of cardiac GRK2 levels by increased catecholamine levels, we describe that systemic insulin resistance-inducing conditions such as high dietary fat also cause enhanced GRK2 expression in the heart.…”

“…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.…”

Targeting the β-Adrenergic Receptor System Through G-Protein–Coupled Receptor Kinase 2: A New Paradigm for Therapy and Prognostic Evaluation in Heart Failure

“…35 In this regard, it has been demonstrated that GRK2, via ␤-arrestin1, regulates angiotensin II type I receptors 46,47 and that GRK2 overexpression promotes insulin resistance after MI. 48 Thus, the favorable effects of GRK2 inhibition in cardiac disease can be ascribed not only to the direct improvement of adrenergic response but also to more complex interactions among different and specific systems involved in the pathophysiological response to myocardial injury. (2) The "therapeutic potential" of GRK2 modulation rises from the availability of the specific inhibitory peptide, ␤ARKct.…”

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

“…In addition, our laboratory and others have found GRK2 to be a negative regulator of glucose uptake (27,28). This may be of particular functional relevance to the glycolytic EDL muscle; it is possible that altering glucose homeostasis by GRK2 ablation in the skeletal muscle may result in a metabolic reprogramming, which in turn could affect energy production and muscle contractile properties as a consequence.…”