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A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure.

Abstract：

:Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.

journal_name

Nat Med

journal_title

Nature medicine

authors

Liggett SB,Cresci S,Kelly RJ,Syed FM,Matkovich SJ,Hahn HS,Diwan A,Martini JS,Sparks L,Parekh RR,Spertus JA,Koch WJ,Kardia SL,Dorn GW 2nd

doi

10.1038/nm1750

subject

Has Abstract

pub_date

2008-05-01 00:00:00

pages

510-7

issue

5

eissn

1078-8956

issn

1546-170X

pii

nm1750

journal_volume

14

pub_type

杂志文章

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