**3.2 GRKs in heart failure**

Myocardial GRK2 and GRK5 have been shown to be involved in the pathophysiology of heart failure [40]. Indeed, several evidences highlight GRK2 as well as GRK5 as the key regulators of β-adrenoceptor [59, 60]. Of importance, recently published paper describes that GRK2 and GRK5 are new therapeutic targets for pathological cardiac hypertrophy and may attenuate morbidity and mortality rates [61]. Dysregulation of β-adrenoceptor is a pathological characteristic of heart failure; in particular, the receptors are considerably downregulated and desensitized as a result of the upregulated levels of GRK2 and GRK5 [16]. Enhanced expression and activity of GRK2 are associated with the loss of β-adrenoceptor functions that induces deleterious effects in the heart functionality contribute to progression of heart failure [62]. Overstimulation of β-adrenoceptor as a subsequent of continuous sympathetic activation, resulting in GRK and β-arrestins induced desensitization and downregulation of β-adrenoceptor [63]. Initially, this process is adaptive response to overcome receptor

overactivation. However, prolonged excessive stimulation mediated receptor downregulation has been reported inducing harmful effect to the heart and consequently heart failure development [63, 64]. Notably, alterations in GRKs have been observed in heart failure [39, 65, 66]. Indeed, several evidences highlight GRK2 as well as GRK5 as the key regulators of β-adrenoceptor [59, 60]. Several reported evidence have shown that GRK2 expression and activity are significantly increased in the failing heart [39, 67, 68]. Enhanced GRK2 expression and altered functionality have been found in heart failure status [39, 65, 66, 69]. Moreover, up-regulation of GRK2 level was detected in end-stage dilated heart failure patient [65]. Even though the mechanism of β-adrenoceptor overstimulation mediated GRK2 upregulation is not clearly understood, published reports show that GRK2 dysfunction plays an essential function in the pathophysiology of heart failure [70] suggesting that alteration in GRK2 function participates in heart failure pathology. Altered GRK2 expression or activity appears to contribute to disease progression through various molecular mechanisms. Therefore, targeting GRK2 expression or inhibition of its activity has been suggested as a therapeutics strategy for treatment of heart failure patients [71, 72].

Reported evidence shows that overexpression of a peptide inhibitor of GRK2; carboxy terminal domain (βARKct) which lacks to membrane translocation function inhibits GRK2 activity and prevents desensitization of the receptors resulting in restoring of β-adrenoceptor function and enhanced cardiac contractility in experimental animals of heart failure [73–75]. Moreover, Gβγ-GRK2 inhibition reduces pathological effect of myofibroblast activation. Thus, Gβγ-GRK2 inhibition might be a potential therapeutic strategy to attenuate pathological myofibroblast activation, interstitial fibrosis, cardiac remodeling, and progression of heart failure [76].

It has been reported that cardiac dysfunction could be attenuated by inhibition of GRK2 activity [62]. Interestingly, it has been reported that paroxetine, selective serotonin re-uptake inhibitor (SSRI) approved by FDA for treatment of depression, significantly inhibited GRK2 kinase activity [49, 77, 78]. Published studies showed capability paroxetine as GRK2 inhibitor in reversing cardiac remodeling in experimental models of acute myocardial infarction [79, 80]. Therefore, paroxetine may perhaps be used as a therapeutic approach for targeting GRK2 catalytic activity and potentially provide a protective role against cardiac hypertrophy development via its function as GRK2 inhibitor.

GRK5 another GRK member that mediates phosphorylation and desensitization of β-adrenoceptor is well known to regulate heart functions [72]. Several studies suggest that GRK5 plays a crucial role in various cardiovascular diseases. For instance, previous studies show that GRK5 overexpressing mice developed cardiac hypertrophy, which rapidly progressed to heart failure [81]. Moreover, GRK5 knockout mice showed attenuated hypertrophic responses [82]. Furthermore, GRK5 overexpressing mice showed an alteration in myocardial performance including attenuation of contractility, cardiac output, stroke work, and stroke volume [83]. Of note, GRK5 levels were shown to be markedly elevated in heart failure patients and patients with left ventricular volume overload disorders and dilated cardiomyopathic hearts [84–86].

GRK5 overexpressed transgenic mice exhibited enhanced susceptibility to pressure overload-induced cardiac hypertrophy and cardiac dysfunction [87]. Furthermore, cardiac-specific GRK5 transgenic mice demonstrated reduced cardiac function and increased adverse cardiac remodeling in a myocardial infarctioninduced heart failure mice model [64]. On other hand, heart hypertrophic responses were attenuated in GRK5 knockout mice [88], these studies demonstrated the possible functions of GRK5 in pathological cardiac remodeling development. Interestingly,

#### *DOI: http://dx.doi.org/10.5772/intechopen.105403 G Protein-Coupled Receptor Regulation in Cardiovascular Disease: Role of G Protein-Coupled…*

several lines of evidence show that GRK5 can translocate to the nucleus, exerting its non-canonical functions. For instance, it was shown that GRK5 in the cardiomyocyte nuclei acts as a class II histone deacetylase (HDAC) kinase, phosphorylating HDAC5 and leading to de-repression of myocyte enhancer factor 2 (MEF2)-mediated hypertrophic gene transcription [81, 89]. In addition, it was demonstrated that GRK5 interacts with hypertrophic transcription factors like nuclear factor of activated T cell (NFAT) and nuclear factor κ-B (NF-κB) [81, 87, 90, 91]. These studies indicate that GRK5 has a major role in the pathogenesis of the cardiovascular disorders and GRK5 might be a therapeutic target for heart failure. Recently, it has been demonstrated that KR-39038, a novel small molecule inhibitor of GRK5, significantly inhibited cellular hypertrophy and HDAC5 phosphorylation in neonatal rat ventricular myocytes. This inhibitor was able to minimize the left ventricular weight, improve cardiac function and ameliorate myocardial remodeling in animal model of heart failure [92]. Another important agent proposed as a GRK5 inhibitor is an anti-inflammatory and anti-allergic immunomodulator, named amlexanox [93]. This agent was able to inhibit GRK5 induced MEF2 activation in neonatal rat ventricular myocytes and inhibit GRK5 mediated HDAC5 phosphorylation in cellular model of cardiac hypertrophy [93, 94].

#### **3.3 GRKs in myocardial infarction**

It has been reported that GRK2 expressions upregulated in peripheral blood lymphocytes in patients with acute ST-segment elevation myocardial infarction. Enhanced lymphocyte GRK2 expressions are associated with worse cardiac functionality. These studies indicate that GRK2 could be predictive of myocardial remodeling after myocardial infarction [95, 96]. Enhanced GRK2 levels and activity are deleterious to post-ischemic myocardium in acute ischemia/reperfusion (I/R) injury animal model [97]. It has been reported that GRK2 peptide inhibitor; βARKct provides cardioprotective effect, which modulate GRK2-mediated PI3K-Akt-NOS signaling pathway in the ischemic heart which validates GRK2-related effect on survival and apoptotic signaling in the ischemic heart [97]. βARKct expression mediated GRK2 inhibition modulate Akt downstream pro-survival signaling such as reduced Caspase-3 activity, increased eNOS activation and NO production and then reduced apoptosis and cell death [97]. Furthermore, decreasing GRK2 expression in cardiomyocytes attenuate myocyte apoptosis possibly via Akt/Bcl-2 mediated mitochondrial protection and limits I/R- provoked injury and improves post-ischemia recovery in the heart [98]. Additionally, it has been reported that fibroblast specific GRK2 knockout has a protective effect after myocardial I/R injury in mice. GRK2 fibroblast knockout mice decreased the infarct size, increased ejection fraction, preserved cardiac function, and also reduced tumor necrosis factor-α expression, fibrotic gene expression, and fibrosis development [99].

## **4. Conclusions**

Cardiovascular diseases are a leading cause of death worldwide. The pathophysiological mechanisms are regulated by a GPCR mediated complex network of transduction pathways. The functions of GRKs, negative regulators of GPCR, are not limited to receptors desensitization. It is expanded further to activations of many transductions in non-classical manner. As the expression and kinase activity of GRK2 and GRK5 are altered in cardiovascular diseases, Therefore, better knowledge of the

transduction events which mediated by up-regulated GRK2 and/or GRK5 in terms of the expression, activity, and localization would help to develop a novel strategy for targeting their expressions or inhibiting activity. This will participate in building a knowledge-based platform identifying a new therapeutic target to prevent the progression of cardiovascular diseases. Many different approaches could be applied, including small molecule inhibitors, gene therapy, and the use of advanced drug delivery systems to potentially prevent the progression of cardiovascular disease. Overall, GRKs play an important role in cardiovascular diseases progression. Pharmacological intervention of GRK5 as well as GRK2 would provide a novel possible future target for cardiovascular disease progression prevention.
