β₂ARs: double edge sword in heart function

Abstract

Deng and colleagues highlight the importance of understanding the divergent roles of β2-adrenoceptor (β₂AR) in high-fat diet-induced heart failure. β₂AR signaling has beneficial and detrimental effects depending on the context and level of activation. We discuss the importance of these findings and their implications in developing effective and safe therapies.

Cardiac cell types

Several resident cell types in the heart differentiate into varying cardiac lineages. The heart comprises four main cell types: cardiac myocytes, fibroblasts, endothelial, and smooth muscle cells (Figure 1). However, several additional players affect tissue remodeling and energetics that are key to overall heart function, including cardiac stem cells, Purkinje cells, and immune cells. New research highlights the need to consider the distinct effects of pharmacological targets on different cardiac cell types to enhance treatment efficacy and reduce off-target effects.

Figure 1. β2-adrenoceptor (β₂AR) function is cell type-specific, as published by Deng et al. [1].

The yellow section on the left of the ^figure illustrates the roles of β₂AR in cardiomyocytes (from β₂AR-cKO mice) subjected to a high-fat diet (HFD). The blue section on the right displays an opposing phenotype of cardiac myofibroblasts (from β₂AR-fKO mice) under the same diet. In the far-right panel, there are other auxiliary cells that interact with cardiomyocytes and are crucial for heart structure and function, which necessitate additional research to determine the expression and function of β₂AR. This figure was created using BioRender.

In recent findings published in Circulation Research, Deng and colleagues [1] highlight the potential dichotomy of cell type-specific actions of β₂AR in cardiac remodeling (Figure 1). The authors found that while myocyte-specific knockout of β₂AR exacerbated high-fat diet (HFD)-induced heart failure (HF), myofibroblast-specific deletion of β₂AR improved HFD-induced HF compared with wild-type littermates. These findings suggest that β₂AR function is cell type-specific, highlighting some complexity in using this G protein-coupled receptor (GPCR) in HF treatments (Figure 1).

GPCRs in HF treatment

GPCRs are diverse, seven-transmembrane receptors that make up the largest family of membrane receptors. GPCRs mediate a myriad of cellular responses, including cytokines, hormones, neurotransmitters, and metabolites. Currently, more than 34% of US FDA-approved drugs are effective targets against GPCRs in various diseases [2]. Classical downstream signaling of GPCRs is well defined, whereupon binding to an agonist ligand, GPCRs interact with heterotrimeric G proteins, which consist of α, β, and γ subunits. This diversity in G-protein subfamilies allows for distinctive regulatory functions in signal transduction, which activates downstream signaling effectors. How drugs modulate GPCR signaling is of importance in the study conducted by Deng and colleagues [1]. However, one limitation of GPCR treatments is that they can affect the functioning of cardiac cells differently and may have off-target effects that could impact a patient’s overall health.

In the context of HF and glucose intolerance, there are several antagonists for GPCRs [2], like beta-adrenergic agonists β₂AR. Beta-adrenergic signaling is a critical regulator of cardiovascular function and has been implicated in the pathophysiology of HF. The beta adrenoreceptor family includes three distinct subtypes, β1, β2, and β3. As GPCRs, β₂ARs are activated by catecholamines epinephrine and norepinephrine and mediate various cellular responses, including modulation of contractility, ion channel activity, and gene expression [3,4]. After activation of these GPCRs, GPCR kinases (GRKs) phosphorylate activated GPCRs, which promotes the recruitment of beta-arrestin (β-arrestin) to regulate the duration and intensity of GPCR signaling and prevent overstimulation of the signaling pathway. β-arrestin binds to the phosphorylated GPCR and desensitizes the receptor [2,4]. Of note, regarding β₂ARs, the role of β-arrestins can vary with each cell type and play a role in both the activation and desensitization of β-AR signaling [2,4].

The role of β₂ARs in cardiac function

In systolic HF with reduced ejection fraction (EF), some studies suggest that targeting β₂AR is superior to β₁AR due to its mortality reduction benefits [3]. EF is a clinical measure that determines how efficiently the heart pumps, where an EF of less than 40% may indicate HF. Furthermore, the cardiac protective role of β₂AR has been well established [3], which supports targeting this receptor for therapeutics. Interestingly, β₂AR has two conformations, confirmed by X-ray crystallization associated with its receptor function [5]. This complex relationship between β₂AR agonist and the GPCR exists, so several inactive confirmations may explain the heterogeneity in downstream response in different cell types or under other conditions. Moreover, the complexity of this signaling should be investigated in therapeutics for HF treatment. However, it is still unclear if β₂AR is beneficial or detrimental in HF, which highlights the novelty of the findings provided by Deng and colleagues [1].

New evidence of cell type-specific roles of β₂AR

β₂ARs play a role in regulating cardiac function and adaptation to stress. β₂AR signaling in cardiomyocytes regulates autophagy, which plays a crucial role in maintaining cellular homeostasis and preventing apoptosis. However, excessive or chronic activation of β₂AR in cardiomyocytes has been linked to adverse outcomes, including arrhythmias and HF [6]. Studies have demonstrated that activation of β₂ARs in cardiomyocytes increases contractility and promotes cardiac hypertrophy, a compensatory response to increased workload or injury that can eventually lead to HF [6]. Another study showed that chronic β₂AR activation in cardiomyocytes induces pathological cardiac hypertrophy and fibrosis, leading to HF [3]. While β₂ARs are expressed in cardiomyocytes, they are also expressed in non-myocyte cells, including fibroblasts and myofibroblasts. Myofibroblasts are specialized regulators of the extracellular matrix. Activation of β₂ARs in myofibroblasts has been shown to stimulate extracellular matrix production and promote fibrosis and cardiac dysfunction in a mouse model of pressure overload-induced HF [7]. β₂AR activation in myofibroblasts had previously been shown to increase the expression of profibrotic genes via the AKT and ERK signaling pathways [3,4]. Interestingly, β₂ARs also have a broader role in metabolism and glucose uptake by myocytes [8] and they may be involved in the recruitment of immune cells to promote healing after acute cardiac injury [9]. However, inflammation can lead to a fibrotic phenotype in the heart and muscle [9]. Given the diversity of β₂AR signaling in cardiac function, it is important to mention that genetic variants could potentially modify the structure and function of the β₂AR gene. For example, β₂AR polymorphisms, or genetic variants, have been linked to cardiovascular disease risk, cardiac function, and obesity [10]. Together this new evidence emphasizes the incredible importance of understanding β₂AR signaling in all cardiac cell types.

Concluding remarks

Deng and colleagues provide a novel perspective outlining the divergent actions of β₂AR in HFD-induced HF and fibrotic remodeling and dysfunction, suggesting that more attention should be given to the pharmacodynamics of therapeutic targets for β₂AR [1] (Figure 1). A better understanding of β2AR signaling is needed to delineate safe and effective treatments for HF. Given the differing effects of β₂AR signaling and activation between cardiac myocytes and myofibroblasts [1] (Figure 1), this presents to the field the limitations of our current understanding of this GPCR. In addition, further investigation is needed to understand β₂AR in other cardiac and non-cardiac cell types (Figure 1). New insights into β₂AR mechanisms could provide more efficacious treatment for HF.