Titre du document / Document title

β¹-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure

Auteur(s) / Author(s)

PEREZ Jeanne Mialet ; RATHZ Deborah A. ; PETRASHEVSKAYA Natalia N. ; HAHN Harvey S. ; WAGONER Lynne E. ; SCHWARTZ Arnold ; DORN Gerald W. ; LIGGETT Stephen B. ;

Résumé / Abstract

Catecholamines stimulate cardiac contractility through β¹-adrenergic receptors (β¹-ARs), which in humans are polymorphic at amino acid residue 389 (Arg/Gly). We used cardiac-targeted transgenesis in a mouse model to delineate mechanisms accounting for the association of Arg389 with human heart failure phenotypes. Hearts from young Arg389 mice had enhanced receptor function and contractility compared with Gly389 hearts. Older Arg389 mice displayed a phenotypic switch, with decreased β-agonist signaling to adenylyl cyclase and decreased cardiac contractility compared with Gly 389 hearts. Arg389 hearts had abnormal expression of fetal and hypertrophy genes and calcium-cycling proteins, decreased adenylyl cyclase and Gas expression, and fibrosis with heart failure This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to β-receptor blockade were greater in Arg389 mice, and homozygosity for Arg389 was associated with improvement in ventricular function during carvedilol treatment in heart failure patients. Thus the human Arg389 variant predisposes to heart failure by instigating hyperactive signaling programs leading to depressed receptor coupling and ventricular dysfunction, and influences the therapeutic response to β-receptor blockade.

Revue / Journal Title

Nature medicine    ISSN  1078-8956 

Source / Source

2003, vol. 9, n^o10, pp. 1300-1305 [6 page(s) (article)]

Langue / Language

Anglais

Editeur / Publisher

Nature Publishing Group, New York, NY, ETATS-UNIS  (1995) (Revue)

Localisation / Location

INIST-CNRS, Cote INIST : 26326, 35400011244739.0080