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GRK2 as a therapeutic target for heart failure
Alessandro Cannavo1,2, Klara Komici2, Leonardo Bencivenga2
1a Center for Translational Medicine , Temple University Lewis Katz School of Medicine , Philadelphia , PA , USA.
Introduction:
G protein-coupled receptor (GPCR) kinase-2 (GRK2) is a regulator of GPCRs, in particular β-adrenergic receptors (ARs), and as demonstrated by decades of investigation, it has a pivotal role in the development and progression of cardiovascular disease, like heart failure (HF). Indeed elevated levels and activity of this kinase are able to promote the dysfunction of both cardiac and adrenal α- and β-ARs and to dysregulate other protective signaling pathway, such as sphingosine 1-phospate and insulin. Moreover, recent discoveries suggest that GRK2 can signal independently from GPCRs, in a 'non-canonical' manner, via interaction with non-GPCR molecule or via its mitochondrial localization. Areas covered: Based on this premise, GRK2 inhibition or its genetic deletion has been tested in several disparate animal models of cardiovascular disease, showing to protect the heart from adverse remodeling and dysfunction. Expert opinion: HF is one of the leading cause of death worldwide with enormous health care costs. For this reason, the identification of new therapeutic targets like GRK2 and strategies such as its inhibition represents a new hope in the fight against HF development and progression. Herein, we will update the readers about the 'state-of-art' of GRK2 inhibition as a potent therapeutic strategy in HF.
Insights
Inhibiting G protein-coupled receptor kinase-2 (GRK2) shows promise for treating heart failure (HF). Studies in animal models demonstrate GRK2 inhibition protects the heart from damage, offering new therapeutic hope for cardiovascular disease.
Area of Science:
- Cardiovascular Disease Research
- Molecular Pharmacology
- Biochemistry
Background:
- G protein-coupled receptor kinase-2 (GRK2) regulates G protein-coupled receptors (GPCRs), notably β-adrenergic receptors (ARs).
- Elevated GRK2 activity contributes to cardiovascular disease, including heart failure (HF), by impairing cardiac and adrenal AR function and other signaling pathways.
- Emerging evidence indicates GRK2 possesses non-canonical signaling roles, independent of GPCRs, through interactions with other molecules or mitochondrial localization.
Purpose of the Study:
- To review the current state of GRK2 inhibition as a therapeutic strategy for heart failure.
- To highlight the protective effects of GRK2 inhibition or deletion in preclinical models of cardiovascular disease.
Main Methods:
- Review of studies involving GRK2 inhibition or genetic deletion in animal models of cardiovascular disease.
- Analysis of GRK2's role in GPCR regulation and non-canonical signaling pathways.
Main Results:
- GRK2 inhibition and genetic deletion have demonstrated cardioprotective effects in various animal models of cardiovascular disease.
- These interventions mitigate adverse cardiac remodeling and improve cardiac function.
Conclusions:
- GRK2 represents a promising therapeutic target for heart failure.
- Inhibition of GRK2 offers a potential new strategy to combat the development and progression of HF, a leading cause of mortality worldwide.
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