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

被引:91
作者
Dzimiri, N
Muiya, P
Andres, E
Al-Halees, Z
机构
[1] King Faisal Specialist Hosp & Res Ctr, Dept Biol & Med Res, Cardiovasc Pharmacol Unit, Riyadh 11211, Saudi Arabia
[2] King Faisal Specialist Hosp & Res Ctr, Dept Biol & Med Res, Pharmacogenom Unit, Riyadh 11211, Saudi Arabia
[3] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Pharmacogenom Unit, Riyadh 11211, Saudi Arabia
[4] King Faisal Specialist Hosp & Res Ctr, Dept Cardiovasc Dis, Riyadh 11211, Saudi Arabia
关键词
G protein-coupled receptor kinase; adenylyl cyclase; beta-Adrenoceptor; protein kinase; human myocardial tissue; hemodynamic load; left ventricular volume overload;
D O I
10.1016/j.ejphar.2004.03.015
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The relationship between myocardial G protein receptor kinase (GRK) expression and beta-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 p-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 beta(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. (C) 2004 Elsevier B.V. All rights reserved.
引用
收藏
页码:167 / 177
页数:11
相关论文
共 42 条
[1]   BETA-ADRENERGIC-RECEPTOR KINASE - PRIMARY STRUCTURE DELINEATES A MULTIGENE FAMILY [J].
BENOVIC, JL ;
DEBLASI, A ;
STONE, WC ;
CARON, MG ;
LEFKOWITZ, RJ .
SCIENCE, 1989, 246 (4927) :235-240
[2]   BETA-ADRENERGIC-RECEPTOR KINASE - IDENTIFICATION OF A NOVEL PROTEIN-KINASE THAT PHOSPHORYLATES THE AGONIST-OCCUPIED FORM OF THE RECEPTOR [J].
BENOVIC, JL ;
STRASSER, RH ;
CARON, MG ;
LEFKOWITZ, RJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (09) :2797-2801
[3]  
BOHM M, 1992, J CARDIOVASC PHARM, V20, P479
[4]  
BOUVIER M, 1989, J BIOL CHEM, V264, P16786
[5]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[6]  
BRISTOW MR, 1992, BASIC RES CARDIOL, V87, P15
[7]   MYOCARDIAL BETA-ADRENOCEPTOR CHANGES IN HEART-FAILURE - CONCOMITANT REDUCTION IN BETA-1-ADRENOCEPTOR AND BETA-2-ADRENOCEPTOR FUNCTION RELATED TO THE DEGREE OF HEART-FAILURE IN PATIENTS WITH MITRAL-VALVE DISEASE [J].
BRODDE, OE ;
ZERKOWSKI, HR ;
DOETSCH, N ;
MOTOMURA, S ;
KHAMSSI, M ;
MICHEL, MC .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1989, 14 (02) :323-331
[8]   Diminished responsiveness of Gs-coupled receptors in severely failing human hearts:: No difference in dilated versus ischemic cardiomyopathy [J].
Brodde, OE ;
Vogelsang, M ;
Broede, A ;
Michel-Reher, M ;
Beisenbusch-Schafer, E ;
Hakim, K ;
Zerkowski, HR .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1998, 31 (04) :585-594
[9]  
Chen G, 2001, MICROSCALE THERM ENG, V5, P71
[10]   Mechanism of beta-adrenergic receptor desensitization in cardiac hypertrophy is increased beta-adrenergic receptor kinase [J].
Choi, DJ ;
Koch, WJ ;
Hunter, JJ ;
Rockman, HA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (27) :17223-17229