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Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure.

Authors: Mialet Perez, J  Rathz, DA  Petrashevskaya, NN  Hahn, HS  Wagoner, LE  Schwartz, A  Dorn, GW  Liggett, SB 
Citation: Mialet Perez J, etal., Nat Med 2003 Oct;9(10):1300-5. Epub 2003 Sep 14.
Pubmed: (View Article at PubMed) PMID:14502278
DOI: Full-text: DOI:10.1038/nm930

Catecholamines stimulate cardiac contractility through beta(1)-adrenergic receptors (beta(1)-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 beta-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 G alpha(s) expression, and fibrosis with heart failure This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to beta-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 beta-receptor blockade.


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CRRD Object Information
CRRD ID: 737774
Created: 2004-02-26
Species: All species
Last Modified: 2004-02-26
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.