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Characterization Of Lymphocyte β 2 ‐Adrenoceptor Signalling In Patients With Left Ventricular Volume Overload Disease
Author(s) -
Dzimiri Nduna,
Basco Chona,
Moorji Azadali,
Afrane Barima,
AlHalees Zohair
Publication year - 2002
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1046/j.1440-1681.2002.03625.x
Subject(s) - adenylyl cyclase , g protein coupled receptor kinase , medicine , endocrinology , forskolin , beta adrenergic receptor kinase , pressure overload , receptor , kinase , basal (medicine) , lymphocyte , messenger rna , adrenergic receptor , biology , heart failure , chemistry , g protein , g protein coupled receptor , microbiology and biotechnology , gene , biochemistry , cardiac hypertrophy , insulin
SUMMARY 1. Studies using animal experimental models have suggested that the β 2 ‐adrenoceptor is uncoupled in association with alterations in the expression of G‐protein‐coupled receptor kinases (GRK) 2/3 in heart failure. However, the functional expression of the components of this pathway in human disease has not been fully elucidated yet. In the present study, we evaluated the possibility that the regulation of β 2 ‐adrenoceptor signalling components in patients with left ventricular volume overload (VOL) depends on the severity of the overload. 2. We characterized the lymphocyte GRK 2–6, β ‐arrestins 1 and 2, β 2 ‐adrenoceptor expression at the mRNA and protein levels, as well as the activity of adenylyl cyclase, protein kinases (PK) A and PKC in patients with VOL using healthy blood donors as controls. 3. In the patient group, GRK2 mRNA was increased by 61% ( P < 0.001), GRK3 was increased by 54% ( P < 0.005), GRK5 was increased fivefold ( P < 0.001) and the β ‐arrestin 2 mRNA was increased by 40% ( P < 0.05). These increases were paralleled with a sixfold increase in GRK2, a twofold increase in GRK3 and a 1.3‐fold increase in GRK5 protein levels. These changes were associated with a significant decrease in β 2 ‐adrenoceptor mRNA, the basal, catalytic and receptor‐mediated activity of adenylyl cyclase and sensitization of the forskolin‐stimulated activity towards augmented inhibition by guanylimidodiphosphate. In general, the increase in GRK2 and 5 mRNA exhibited a positive correlation with the gravity of the haemodynamic load, as determined by changes in left ventricular fractional shortening. 4. The results suggest that VOL induces an increase in the expression of lymphocyte β 2 ‐adrenoceptor‐specific GRK and β ‐arrestin 2 in association with an attenuation in β 2 ‐adrenoceptor levels. It can be speculated that the cardiac circulatory system adapts itself to altered haemodynamic functional demands partly by altering β 2 ‐adrenoceptor signalling.