GRK2 as a therapeutic target for heart failure

ABSTRACT

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.

KEYWORDS:

• G protein-coupled receptor
• GRK2
• gene-therapy
• heart failure

Article highlights

• GRK2 is a serine/threonine kinase controlling the function of most of GPCRs present on either cardiomyocytes and non-cardiomyocytes and is involved in regulation of overall cardiovascular physiology.

• Global GRK2 knockout causes hypoplasia of the ventricular myocardium with embryonic lethality while GRK2 overexpression accelerates the development of heart failure in response to an ischemic stress.

• Non-canonical noxious activities of GRK2 mainly include the interaction and inhibition of IRS1 and the localization to the mitochondria.

• GRK2, canonical and non-canonical activities, can be selectively inhibited through specific molecules such as the CT-derived peptide βARKct.

• Paroxetine and its derived compounds exhibit high selectivity for GRK2 and have been found to enhance cardiac contractility encouraging a possible clinical study in humans

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Italian Ministry of Health (GR-2011-02346878) and Compagnia di San Paolo and Istituto Banco di Napoli - Fondazione and University of Naples Federico II- STAR program 2016, both awarded to G. Rengo.