GRK5 inhibition as a promising strategy in heart failure therapy

Background: The G protein-coupled receptor kinase 5 (GRK5) phosphorylates and thereby desensitizes G protein-coupled receptors (GPCRs). Studies suggest that GRK5 is a promising target for heart failure therapy, as it appears to influence maladaptive cardiac remodeling through both canonical and non-canonical pathways. However, no specific GRK5 inhibitor has yet been developed for clinical use. 

Aim: The aim of this project is to evaluate the therapeutic potential of GRK5 inhibitor derivatives for oral administration in a heart failure model including the assessment of their efficacy and toxicity in vitro and in vivo. The inhibitors were developed based on compounds that were successfully tested in a previous i.p. study. 

Methods and results: The daily administration of GRK5 inhibitors was started one week after induction of chronic left ventricular pressure overload via transverse aortic constriction (TAC) and continued for four weeks. Treatment with GRK5 inhibitors resulted in a significantly attenuated increase in left ventricular posterior wall thickness after TAC compared to control treated mice (1 ± 0.1 mm vs. 0.8 ± 0.01 mm). Also, the decrease in fractional shortening upon TAC was significantly reduced in GRK5 inhibitor-treated mice (21 ± 4.9% vs. 33 ± 7.2%). Real-time PCR (qPCR) analyses of cardiac tissue revealed that GRK5 inhibition reduced the expression of genes associated with cardiac remodeling, such as atrial natriuretic peptide (ANP) and Col3a1 by about 75% and 60%, respectively. Interestingly, also GRK5 mRNA expression was significantly reduced. In in vitro analyses in neonatal mouse cardiomyocytes, we evaluated the compounds' impact on cardiac stress by the assessment of isoproterenol-induced beating irregularities using impedance-based readouts. Interestingly, GRK5 inhibition effectively reduced isoproterenol-induced arrhythmic beating.

Conclusion: We demonstrated that orally active GRK5 inhibitors ameliorated cardiac function after induction of heart failure by TAC. The inhibitors effectively downregulated the expression of key genes linked to cardiac remodeling. Moreover, the reduction in arrhythmic events under stress in vitro reinforces the potential of GRK5 inhibition as a promising strategy for heart failure treatment.