Differential functional expression of human myocardial G protein receptor kinases in left ventricular cardiac diseases

Abstract

The relationship between myocardial G protein receptor kinase (GRK) expression and β-adrenoceptor signalling in human left heart diseases has not been fully elucidated yet. In this study, we characterized and compared the GRK2–7 expression in patients with left ventricular volume overload disorders and dilated cardiomyopathic hearts, and evaluated the relationship of this expression with alterations in myocardial β-adrenoceptor signalling in volume overload, in order to test the notion that GRK functional expression is influenced in a disease-specific and selective fashion. We established that GRK2, GRK3, and GRK5 are well expressed, while GRK4, GRK6, and GRK7 are only scarcely detectable in the healthy human heart. Compared to control hearts ( n=8), GRK2 mRNA expression was elevated by 71% ( P<0.005) in the left ventricle, 110% ( P<0.05) in the right ventricle, 130% ( P<0.05) in the left atrium, and 1300% ( P<0.005) in the right atrium (RA) of the dilated cardiomyopathy hearts ( n=6). In the volume overload group ( n=10), it was increased by approximately 40% ( P<0.05) in the left ventricle, 38% in the right ventricle, 81% ( P<0.05) in the left atrium, and 850% ( P<0.005) in the right atrium. On the other hand, GRK5 was significantly elevated only in the left ventricle by 68% ( P<0.05) in the dilated cardiomyopathy hearts and by 48% ( P<0.01) in volume overload patients, while in contrast, GRK3 remained unchanged in dilated cardiomyopathy, but was slightly elevated by 36% ( P=0.05) in the right ventricle of the volume overload patients. The alterations in GRK expression were accompanied with a decrease in myocardial β 1-adrenoceptor mRNA in all four chambers, and these trends in gene expression were paralleled with those of their immunodetectable protein levels. Furthermore, these changes were in association with a decrease in downstream receptor-stimulated, adenylyl cyclase-mediated functional expression and an increase in ventricular protein kinase A activity. The results point to differences in which myocardial GRKs are regulated in cardiac disease, whereby changes in GRK2 expression may be related to the global effects of the disease on myocardial adrenoceptor function and those in GRK5 may be localized to the ventricles, depending on the nature of the myocardial load.