ABSTRACT
Introduction: One in every four deaths in the United States is attributed to cardiovascular disease, hence the development and employment of novel and effective therapeutics are necessary to improve the quality of life and survival of affected patient. Pathological hypertrophy is a maladaptive response by the heart to relieve wall stress that could result from cardiovascular disease. Maladaptive hypertrophy can lead to further disease progression and complications such as heart failure; hence, efforts to target hypertrophy to prevent and treat further morbidity and mortality are necessary.
Areas covered: This review summarizes the compelling literature that describes the mechanistic role of GRK2 and GRK5 in maladaptive cardiac hypertrophy; it examines the approaches to inhibit these kinases in hypertrophic animal models and furthermore, it assesses the potential of GRK2 and GRK5 as therapeutic targets for hypertrophy.
Expert opinion: GRK2 and GRK5 are novel therapeutic targets for pathological hypertrophy and may have added benefits of ameliorating morbidity and mortality. Despite the lesser researched role of GRK2 in cardiac hypertrophy, it may be the advantageous strategy for treating cardiac hypertrophy because of its role in other maladaptive pathways. Anti-GRK2 therapy optimization and the discovery and development of specific GRK2 and GRK5 small-molecule inhibitors is necessary for the eventual application of successful, effective therapeutics.
Article Highlights
GRKs have been studied extensively in cardiovascular disease, primarily for their role in regulating β-adrenergic receptor-mediated cardiac contraction.
Numerous studies have shed light on the significant influence of GRKs in the mediation of cardiac hypertrophy.
While in vitro studies suggest a direct role for GRK2 in mediating hypertrophy, the majority of published studies using GRK2 overexpression or GRK2 inhibition in animal models, suggest a non-direct role in hypertrophy.
GRK5 has direct pro-hypertrophic roles that are dependent on its nuclear translocation to increase NFAT and NFκB transcriptional activity, in which GRK5 inhibition significantly ablates cardiac hypertrophy in animal hypertrophic models.
Despite GRK2’s debatable direct role in hypertrophy, anti-GRK2 therapy appears to be an attractive and advantageous therapeutic strategy compared to anti-GRK5 therapy.
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Declaration of interest
The authors have no relevant other 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.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose