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Targeting β3-Adrenergic Receptors in the Heart: Selective Agonism and β-Blockade
Alessandro Cannavo1, Walter J Koch
1Department of Pharmacology, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
Insights
Heart failure involves beta-adrenergic receptor (βAR) dysregulation. Targeting the unique β3AR, which resists desensitization, offers a novel strategy for improving cardiac function and remodeling.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Cardiac diseases, particularly heart failure (HF), are major global health issues, often stemming from myocardial infarction.
- HF is linked to β-adrenergic receptor (βAR) dysregulation, specifically over-desensitization of β1 and β2ARs due to increased G protein-coupled receptor kinases, leading to reduced inotropic reserve.
Purpose of the Study:
- To explore the potential of the β3AR as a therapeutic target in cardiac diseases.
- To investigate the role of β3AR in maintaining cardiac function during heart failure.
Main Methods:
- Analysis of βAR expression and desensitization in failing myocardium.
- Review of preclinical studies on β3AR signaling pathways.
- Examination of the link between β-blocker effects and β3AR activity.
Main Results:
- The β3AR isoform is unique as it lacks G protein-coupled receptor kinases recognition sites, preventing desensitization.
- In human failing hearts, β3AR levels remain stable or increase, unlike β1 and β2ARs.
- Preclinical data suggest β3AR activation triggers cardioprotective signaling pathways.
Conclusions:
- The β3AR's resistance to desensitization and its presence in failing hearts make it a promising therapeutic target.
- Targeting β3ARs may offer a novel strategy to enhance cardiac metabolism, improve function, and mitigate adverse remodeling in heart failure.
Abstract:
Cardiac diseases, such as heart failure, remain leading causes of morbidity and mortality worldwide, with myocardial infarction as the most common etiology. HF is characterized by β-adrenergic receptor (βAR) dysregulation that is primarily due to the upregulation of G protein-coupled receptor kinases that leads to overdesensitization of β1 and β2ARs, and this clinically manifests as a loss of inotropic reserve. Interestingly, the "minor" βAR isoform, the β3AR, found in the heart, lacks G protein-coupled receptor kinases recognition sites, and is not subject to desensitization, and as a consequence of this, in human failing myocardium, the levels of this receptor remain unchanged or are even increased. In different preclinical studies, it has been shown that β3ARs can activate different signaling pathways that can protect the heart. The clinical relevance of this is also supported by the effects of β-blockers which are well known for their proangiogenic and cardioprotective effects, and data are emerging showing that these are mediated, at least in part, by enhancement of β3AR activity. In this regard, targeting of β3ARs could represent a novel potential strategy to improve cardiac metabolism, function, and remodeling.
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