Targeting cardiac β-adrenergic signaling via GRK2 inhibition for heart failure therapy

Abstract

Cardiac cells, like those of the other tissues, undergo regulation through membrane-bound proteins known as G protein-coupled receptors (GPCRs). β-adrenergic receptors (βARs) are key GPCRs expressed on cardiomyocytes and their role is crucial in cardiac physiology since they regulate inotropic and chronotropic responses of the sympathetic nervous system (SNS). In compromised conditions such as heart failure (HF), chronic βAR hyperstimulation occurs via SNS activation resulting in receptor dysregulation and down-regulation and consequently there is a marked reduction of myocardial inotropic reserve and continued loss of pump function. Data accumulated over the last two decades indicates that a primary culprit in initiating and maintain βAR dysfunction in the injured and stressed heart is GPCR kinase 2 (GRK2), which was originally known as βARK1 (for βAR kinase). GRK2 is up-regulated in the failing heart due to chronic SNS activity and targeting this kinase has emerged as a novel therapeutic strategy in HF. Indeed, its inhibition or genetic deletion in several disparate animal models of HF including a pre-clinical pig model has shown that GRK2 targeting improves functional and morphological parameters of the failing heart. Moreover, non-βAR properties of GRK2 appear to also contribute to its pathological effects and thus, its inhibition will likely complement existing therapies such as βAR blockade. This review will explore recent research regarding GRK2 inhibition; in particular it will focus on the GRK2 inhibitor peptide known as βARKct, which represents new hope in the treatment against HF progression.

Keywords: G-protein coupled receptors; G-protein-coupled receptor kinase 2; heart failure; β adrenergic system; β blockers.

Figure 1

Differential signaling pathways activated by β₁ARs and β₂ARs in cardiomyocytes. Following SNS catecholamines (Norepinephrine-NE) stimulation, activated β₁ARs and β₂ARs induce the production of cAMP through Gs activation of adenylyl cyclase (AC). Next, cAMP activates PKA resulting in positive chronotropic and inotropic effects. Secondarily, β₁AR through Gs and Calmodulin-dependent kinase (CAMKII) dependent pathway can induce myocyte apoptotic responses after increased catecholamine stimulation. In contrast, β₂ARs can induce the activation of Gi dependent cell survival and anti-apoptotic signaling through Akt. Both β ARs are regulated by GRK2 phosphorylation causing the dampening of G protein activation and chronically this leads to receptor down-regulation and the loss of inotropic reserve. Heightened GRK2 activity, as seen in human HF, appears to have a net pro-death effect due, at least in part to desensitization of β₂ARs (Brinks et al., 2010) and also due to novel GPCR-independent mitochondrial targeting (Chen et al., 2013).

Figure 2

Multiple protective role of βARKct in failing myocardium against high GRK2 levels. Schematic representation of GRK2-inhibition mediated by βARKct: (1) βARKct, like GRK2, binds to G_βγ subunits after GPCR (e.g., βARs) activation and reduces the capability of GRK2 to induce dysregulation/downregulation of these receptors; (2) βARKct antagonizes GRK2 dependent phosphorylation of IRS1 increasing glucose uptake in myocytes; (3) βARKct blocks the ischemia-induced mitochondria localization of GRK2 through inhibition of MAPK-dependent Hsp90 binding, inhibiting pro-apoptotic signaling.