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Alteration of myocardial GRK2 produces a global metabolic phenotype.

ABSTRACT: A vast body of literature has established GRK2 as a key player in the development and progression of heart failure. Inhibition of GRK2 improves cardiac function post injury in numerous animal models. In recent years, discovery of several non-canonical GRK2 targets has expanded our view of this kinase. Here, we describe the novel and exciting finding that cardiac GRK2 activity can regulate whole body metabolism. Transgenic mice with cardiac-specific expression of a peptide inhibitor of GRK2 (Tg?ARKct) display an enhanced obesogenic phenotype when fed a high fat diet (HFD). In contrast, mice with cardiac-specific overexpression of GRK2 (TgGRK2) show resistance to HFD induced obesity. White adipose tissue (WAT) mass was significantly enhanced in HFD fed Tg?ARKct mice. Furthermore, regulators of adipose differentiation were differentially regulated in WAT from mice with gain or loss of GRK2 function. Using complex metabolomics we found that cardiac GRK2 signaling altered myocardial BCAA and endocannabinoid metabolism and modulated circulating BCAA and endocannabinoid metabolite profiles on a HFD, and one of the BCAA metabolites identified here enhances adipocyte differentiation in vitro. Taken together, these results suggest that metabolic changes in the heart due to GRK2 signaling on a HFD control whole body metabolism.

SUBMITTER: Woodall BP

PROVIDER: S-EPMC6542603 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Alteration of myocardial GRK2 produces a global metabolic phenotype.

Woodall Benjamin P BP Gresham Kenneth S KS Woodall Meryl A MA Valenti Mesele-Christina MC Cannavo Alessandro A Pfleger Jessica J Chuprun J Kurt JK Drosatos Konstantinos K Koch Walter J WJ

JCI insight 20190404

A vast body of literature has established GRK2 as a key player in the development and progression of heart failure. Inhibition of GRK2 improves cardiac function post injury in numerous animal models. In recent years, discovery of several non-canonical GRK2 targets has expanded our view of this kinase. Here, we describe the novel and exciting finding that cardiac GRK2 activity can regulate whole body metabolism. Transgenic mice with cardiac-specific expression of a peptide inhibitor of GRK2 (TgβA ...[more]

PMID: 30946029

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Project description:INTRODUCTION:Current metabolomics approaches to unravel impact of diet- or lifestyle induced phenotype variation and shifts predominantly deploy univariate or multivariate approaches, with a posteriori interpretation at pathway level. This however often provides only a fragmented view on the involved metabolic pathways. OBJECTIVES:To demonstrate the feasibility of using Goeman's global test (GGT) for assessment of variation and shifts in metabolic phenotype at the level of a priori defined pathways. METHODS:Two intervention studies with identified phenotype variations and shifts were examined. In a weight loss (WL) intervention study obese subjects received a mixed meal challenge before and after WL. In a polyphenol (PP) intervention study obese subjects received a high fat mixed meal challenge (61E% fat) before and after a PP intervention. Plasma samples were obtained at fasting and during the postprandial response. Besides WL- and PP-induced phenotype shifts, also correlation of plasma metabolome with phenotype descriptors was assessed at pathway level. The plasma metabolome covered organic acids, amino acids, biogenic amines, acylcarnitines and oxylipins. RESULTS:For the population of the WL study, GGT revealed that HOMA correlated with the fasting levels of the TCA cycle, BCAA catabolism, the lactate, arginine-proline and phenylalanine-tyrosine pathways. For the population of the PP study, HOMA correlated with fasting metabolite levels of TCA cycle, fatty acid oxidation and phenylalanine-tyrosine pathways. These correlations were more pronounced for metabolic pathways in the fasting state, than during the postprandial response. The effect of the WL and PP intervention on a priori defined metabolic pathways, and correlation of pathways with insulin sensitivity as described by HOMA was in line with previous studies. CONCLUSION:GGT confirmed earlier biological findings in a hypothesis led approach. A main advantage of GGT is that it provides a direct view on involvement of a priori defined pathways in phenotype shifts.

Project description:BACKGROUND:Cardiac fibroblasts are a critical cell population responsible for myocardial extracellular matrix homeostasis. Upon injury or pathological stimulation, these cells transform to an activated myofibroblast state and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation, a hallmark of heart failure (HF), induces pathological signaling through G protein ?? (G??) subunits and their interaction with G protein-coupled receptor kinase 2 (GRK2). OBJECTIVES:This study investigated the hypothesis that G??-GRK2 inhibition and/or ablation after myocardial injury would attenuate pathological myofibroblast activation and cardiac remodeling. METHODS:The therapeutic potential of small molecule G??-GRK2 inhibition, alone or in combination with activated fibroblast- or myocyte-specific GRK2 ablation-each initiated after myocardial ischemia-reperfusion (I/R) injury-was investigated to evaluate the possible salutary effects on post-I/R fibroblast activation, pathological remodeling, and cardiac dysfunction. RESULTS:Small molecule G??-GRK2 inhibition initiated 1 week post-injury was cardioprotective in the I/R model of chronic HF, including preservation of cardiac contractility and a reduction in cardiac fibrotic remodeling. Systemic small molecule G??-GRK2 inhibition initiated 1 week post-I/R in cardiomyocyte-restricted GRK2 ablated mice (also post-I/R) still demonstrated significant cardioprotection, which suggested a potential protective role beyond the cardiomyocyte. Inducible ablation of GRK2 in activated fibroblasts (i.e., myofibroblasts) post-I/R injury demonstrated significant functional cardioprotection with reduced myofibroblast transformation and fibrosis. Systemic small molecule G??-GRK2 inhibition initiated 1 week post-I/R provided little to no further protection in mice with ablation of GRK2 in activated fibroblasts alone. Finally, G??-GRK2 inhibition significantly attenuated activation characteristics of failing human cardiac fibroblasts isolated from end-stage HF patients. CONCLUSIONS:These findings suggested consideration of a paradigm shift in the understanding of the therapeutic role of G??-GRK2 inhibition in treating HF and the potential therapeutic role for G??-GRK2 inhibition in limiting pathological myofibroblast activation, interstitial fibrosis, and HF progression.

Project description:BACKGROUND:In the months after acute myocardial infarction (MI), risk for acute atherothrombotic events in nonculprit arteries increases several fold. OBJECTIVES:This study investigated whether sustained proinflammatory and prothrombotic endothelial alterations occur in remote vessels after MI. METHODS:Wild-type mice, atherosclerotic mice with double knockout (DKO) of the low-density lipoprotein receptor and Apobec-1, and DKO mice treated with the Nox-inhibitor apocynin were studied at baseline and at 3 and 21 days after closed-chest MI. Ultrasound molecular imaging of P-selectin, vascular cell adhesion molecule (VCAM)-1, von Willebrand factor (VWF) A1-domain, and platelet GPIb? was performed. Intravital microscopy was used to characterize post-MI leukocyte and platelet recruitment in the remote microcirculation after MI. RESULTS:Aortic molecular imaging for P-selectin, VCAM-1, VWF-A1, and platelets was increased several-fold (p < 0.01) 3 days post-MI for both wild-type and DKO mice. At 21 days, these changes resolved in wild-type mice but persisted in DKO mice. Signal for platelet adhesion was abolished 1 h after administration of ADAMTS13, which regulates VWF multimerization. In DKO and wild-type mice, apocynin significantly attenuated the post-MI increase for molecular targets, and platelet depletion significantly reduced P-selectin and VCAM-1 signal. On intravital microscopy, MI resulted in remote vessel leukocyte adhesion and platelet string or net complexes. On histology, high-risk inflammatory features in aortic plaque increased in DKO mice 21 days post-MI, which were completely prevented by apocynin. CONCLUSIONS:Acute MI stimulates a spectrum of changes in remote vessels, including up-regulation of endothelial inflammatory adhesion molecules and platelet-endothelial adhesion from endothelial-associated VWF multimers. These remote arterial alterations persist longer in the presence of hyperlipidemia, are associated with accelerated plaque growth and inflammation, and are attenuated by Nox inhibition.

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Alteration of myocardial GRK2 produces a global metabolic phenotype.

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Alteration of myocardial GRK2 produces a global metabolic phenotype.

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