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Gi-biased ?2AR signaling links GRK2 upregulation to heart failure.

ABSTRACT: RATIONALE:Phosphorylation of ?(2)-adrenergic receptor (?(2)AR) by a family of serine/threonine kinases known as G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) is a critical determinant of cardiac function. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is a well-established causal factor of heart failure, but the underlying mechanism is poorly understood. OBJECTIVE:We sought to determine the relative contribution of PKA- and GRK-mediated phosphorylation of ?(2)AR to the receptor coupling to G(i) signaling that attenuates cardiac reserve and contributes to the pathogenesis of heart failure in response to pressure overload. METHODS AND RESULTS:Overexpression of GRK2 led to a G(i)-dependent decrease of contractile response to ?AR stimulation in cultured mouse cardiomyocytes and in vivo. Importantly, cardiac-specific transgenic overexpression of a mutant ?(2)AR lacking PKA phosphorylation sites (PKA-TG) but not the wild-type ?(2)AR (WT-TG) or a mutant ?(2)AR lacking GRK sites (GRK-TG) led to exaggerated cardiac response to pressure overload, as manifested by markedly exacerbated cardiac maladaptive remodeling and failure and early mortality. Furthermore, inhibition of G(i) signaling with pertussis toxin restores cardiac function in heart failure associated with increased ?(2)AR to G(i) coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of ?(2)AR by GRK and resultant increase in G(i)-biased ?(2)AR signaling play an important role in the development of heart failure. CONCLUSIONS:Our data show that enhanced ?(2)AR phosphorylation by GRK, in addition to PKA, leads the receptor to G(i)-biased signaling, which, in turn, contributes to the pathogenesis of heart failure, marking G(i)-biased ?(2)AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression.

SUBMITTER: Zhu W

PROVIDER: S-EPMC3282829 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Gi-biased β2AR signaling links GRK2 upregulation to heart failure.

Zhu Weizhong W Petrashevskaya Natalia N Ren Shuxun S Zhao Aizhi A Chakir Khalid K Gao Erhe E Chuprun J Kurt JK Wang Yibin Y Talan Mark M Dorn Gerald W GW Lakatta Edward G EG Koch Walter J WJ Feldman Arthur M AM Xiao Rui-Ping RP

Circulation research 20111215 2

<h4>Rationale</h4>Phosphorylation of β(2)-adrenergic receptor (β(2)AR) by a family of serine/threonine kinases known as G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) is a critical determinant of cardiac function. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is a well-established causal factor of heart failure, but the underlying mechanism is poorly understood.<h4>Objective</h4>We sought to determine the relative contribution of PKA- and GRK-mediated phosphoryla ...[more]

PMID: 22179058

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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:Heart failure is the terminal stage of many cardiac diseases, in which β1-adrenoceptor (β1-AR) autoantibody (β1-AA) has a causative role. By continuously activating β1-AR, β1-AA can induce cytotoxicity, leading to cardiomyocyte apoptosis and heart dysfunction. However, the mechanism underlying the persistent activation of β1-AR by β1-AA is not fully understood. Receptor endocytosis has a critical role in terminating signals over time. β2-adrenoceptor (β2-AR) is involved in the regulation of β1-AR signaling. This research aimed to clarify the mechanism of the β1-AA-induced sustained activation of β1-AR and explore the role of the β2-AR/Gi-signaling pathway in this process. The beating frequency of neonatal rat cardiomyocytes, cyclic adenosine monophosphate content, and intracellular Ca2+ levels were examined to detect the activation of β1-AA. Total internal reflection fluorescence microscopy was used to detect the endocytosis of β1-AR. ICI118551 was used to assess β2-AR/Gi function in β1-AR sustained activation induced by β1-AA in vitro and in vivo. Monoclonal β1-AA derived from a mouse hybridoma could continuously activate β1-AR. β1-AA-restricted β1-AR endocytosis, which was reversed by overexpressing the endocytosis scaffold protein β-arrestin1/2, resulting in the cessation of β1-AR signaling. β2-AR could promote β1-AR endocytosis, as demonstrated by overexpressing/interfering with β2-AR in HL-1 cells, whereas β1-AA inhibited the binding of β2-AR to β1-AR, as determined by surface plasmon resonance. ICI118551 biasedly activated the β2-AR/Gi/G protein-coupled receptor kinase 2 (GRK2) pathway, leading to the arrest of limited endocytosis and continuous activation of β1-AR by β1-AA in vitro. In vivo, ICI118551 treatment attenuated myocardial fiber rupture and left ventricular dysfunction in β1-AA-positive mice. This study showed that β1-AA continuously activated β1-AR by inhibiting receptor endocytosis. Biased activation of the β2-AR/Gi/GRK2 signaling pathway could promote β1-AR endocytosis restricted by β1-AA, terminate signal transduction, and alleviate heart damage.

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Gi-biased ?2AR signaling links GRK2 upregulation to heart failure.

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Gi-biased β2AR signaling links GRK2 upregulation to heart failure.

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