© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure
aInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Abteilung für Pharmakologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
bInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Abt. für Klinische Pharmakologie und Toxikologie, Nürnberg, Germany
cMedizinische Klinik und Poliklinik, Universitätsklinikum Regensburg, Regensburg, Germany
dMedizinische Klinik, Universitätsklinikum Göttingen, Göttingen, Germany
eAbteilung für Herz- und Gefässchirurgie, Universität zu Kiel, Kiel, Germany
* Corresponding author. Tel.: +49-40-42803-4707; fax: +49-40-42803-4876
Objective: RGS proteins (regulators of G protein signalling) negatively regulate G protein function as GTPase activating proteins. By controlling heterotrimeric G proteins they may regulate myocardial hypertrophy and contractility. We investigated the expression of RGS proteins in the human heart and whether they take part in the pathophysiological changes of heart failure. Methods and results: Using RNase protection assays (RPAs) RGS2, 3L, 3S, 4, 5 and 6 were identified in the myocardium from terminally failing human hearts with dilated (DCM, n = 22) or ischemic (ICM, n = 18) cardiomyopathy and from nonfailing donor hearts (NF, n = 9). With reverse transcriptase polymerase chain reaction in addition mRNA of RGS1, 9, 12, 14 and 16 were detectable. Compared to NF in failing LV myocardium RGS4 mRNA and protein was upregulated 2–3-fold (mRNA, 10–21 mol/µg±S.E.M.: NF: 22±5
, DCM: 51±10*, ICM: 37±8; P<0.05 vs. DCM+ICM, *P<0.05 vs. NF, P<0.05 vs. DCM+ICM; protein, % of NF±S.E.M.: NF: 100±35, DCM 266±60*, ICM: 205±64, n = 5, *P<0.05 vs. NF). In contrast, RGS2, 3L, 3S, 5, 6, and 16 protein and mRNA levels did not vary between failing and NF hearts. In order to investigate the impact of RGS4 on Gq/11 mediated signalling, PLC activity was measured in human LV membranes. Recombinant RGS4 blunted the endothelin-1 (ET-1) stimulated PLC activity. When overexpressed by adenoviral mediated gene transfer in rabbit ventricular myocytes RGS4 abolished the inotropic effect of ET-1. Conclusion: The upregulation of RGS4 in failing human myocardium diminishes Gq/11-mediated signalling and can be involved in the desensitization of Gq/11-mediated positive inotropic effects.
KEYWORDS Contractile function; Endothelins; G-proteins; Heart failure; Myocytes
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