Canonical or non‐canonical, all aspects of G protein‐coupled receptor kinase 2 in heart failure

Figures

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  FIGURE 1. The Action of GRK2 on Cardiac ΒAR Signaling During Sympathetic Nervous System Hyperactivity in Heart Failure. Upon receptor activation, GRK2 translocates to the membrane and phosphorylates the receptor, triggering G protein uncoupling. β‐arrestins then bind to the phosphorylated receptor, blocking G protein activation, promoting receptor internalization and downregulation, and initiating new signaling pathways. During heart failure, increased catecholamines elevate GRK2 levels, which cause chronic desensitization of β‐adrenergic receptor and pathological effects, contributing to lower cardiac contractile function and heart failure progression. GRK2, G‐protein‐coupled receptor kinase 2; GPCR, G‐protein‐coupled receptor; AC, adenylate cyclase; CA, catecholamines; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; PKA, protein kinase A; βAR, β‐adrenergic receptor.

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  FIGURE 2. Mechanisms Affecting Heart Function via GRK2 in Cardiovascular Pathophysiology. The figure illustrates the various pathways through which GRK2 impacts heart function, particularly in the context of cardiovascular diseases. βAR hyperactivation, indicated by increased GRK2 in cardiomyocytes due to high catecholamine levels, results in reduced βAR responsiveness. Insulin resistance is mediated by GRK2's phosphorylation of IRS1, reducing glucose uptake and causing mitochondrial dysfunction, cardiac fibrosis, and hypertrophy. In diabetic cardiomyopathy, high GRK2 levels are linked to early‐stage diabetic cardiomyopathy and subsequent cardiac dysfunction. Increased GRK2 levels enhance TGF‐β1 activity, leading to increased fibrosis. Additionally, GRK2 desensitizes AdipoR1, reducing the receptor's cytoprotective effects and leading to diminished anti‐inflammatory and anti‐apoptotic activity. GRK2's effects on fatty acid metabolism, lead to lipotoxicity and cardiomyocyte death. Conversely, exercise and mechanical unloading through devices like LVAD reduce GRK2 levels, improving βAR responsiveness and cardiac function. Increased GRK2 activity also correlates with oxidative stress and…

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  FIGURE 3. GRK2: A Key Mediator and Biomarker in Heart Failure Progression. In the early stages of heart failure, elevated GRK2 expression does not directly induce apoptosis. However, as heart failure advances, increased GRK2 expression contributes to various pathological effects, including GPCR desensitization, insulin resistance, heightened βAR stimulation by the SNS, mitochondrial dysfunction, impaired fatty acid oxidation, and ROS production. These processes collectively lead to apoptosis and cardiac fibrosis. Concurrently, heart failure is characterized by reduced myocardial contractility and diminished cardiac output. Elevated GRK2 further exacerbates these effects by inhibiting α2ARs, which regulate catecholamine secretion. This inhibition results in increased epinephrine release, driving cardiac remodeling, apoptosis, and fibrosis, thereby perpetuating the progression of heart failure. GRK2, G‐protein‐coupled receptor kinase 2; GPCR, G‐protein‐coupled receptor; βAR, β‐adrenergic receptor; SNS, sympathetic nervous system; ROS, reactive oxygen species; α2Ars, α2‐adrenergic receptors.