Gene Transfer of Heterologous G Protein–Coupled Receptors to CardiomyocytesDifferential Effects on Contractility
作者:
Karl-Ludwig Laugwitz,
Hans-Jörg Weig,
Alessandra Moretti,
Eva Hoffmann,
Peter Ueblacker,
Ingo Pragst,
Kai Rosport,
Albert Schömig,
Martin Ungerer,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2001)
卷期:
Volume 88,
issue 7
页码: 688-695
ISSN:0009-7330
年代: 2001
出版商: OVID
关键词: gene transfer;receptor;heart failure
数据来源: OVID
摘要:
In heart failure, reduced cardiac contractility is accompanied by blunted cAMP responses to &bgr;-adrenergic stimulation. Parathyroid hormone (PTH)–related peptide and arginine vasopressin are released from the myocardium in response to increased wall stress but do not stimulate contractility or adenylyl cyclase at physiological concentrations. To bypass the defective &bgr;-adrenergic signaling cascade, recombinant P1 PTH/PTH-related peptide receptors (rPTH1-Rs) and V2vasopressin receptors (rV2-Rs), which are normally not expressed in the myocardium and which are both strongly coupled to adenylyl cyclase, and recombinant &bgr;2-adrenergic receptors (r&bgr;2-ARs) were overexpressed in cardiomyocytes by viral gene transfer. The capacity of endogenous hormones to increase contractility via the heterologous, recombinant receptors was compared. Whereas V2-Rs are uniquely coupled to Gs, PTH1-Rs and &bgr;2-ARs are also coupled to other G proteins. Gene transfer of rPTH1-Rs or r&bgr;2-ARs to adult cardiomyocytes resulted in maximally increased basal contractility, which could not be further stimulated by adding receptor agonists. Agonists at rPTH1-Rs induced increased cAMP formation and phospholipase C activity. In contrast, healthy or failing rV2-R–expressing cardiomyocytes showed unaltered basal contractility. Their contractility and cAMP formation increased only at agonist exposure, which did not activate phospholipase C. In summary, we found that gene transfer of PTH1-Rs to cardiomyocytes results in constitutive activity of the transgene, as does that of &bgr;2-ARs. In the absence of receptor agonists, rPTH1-Rs and r&bgr;2-ARs increase basal contractility, coupling to 2 G proteins simultaneously. In contrast, rV2-Rs are uniquely coupled to Gs and are not constitutively active, retaining their property to be activated exclusively on agonist stimulation. Therefore, gene transfer of V2-Rs might be more suited to test the effects of cAMP-stimulating receptors in heart failure than that of PTH1-Rs or &bgr;2-ARs.
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