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Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 1: experimental studies.

Abstract：

:Essential hypertension is a complex, multifactorial disease associated with a high cardiovascular risk and whose genetic-molecular basis is heterogeneous and largely unknown. Although multiple antihypertensive therapies are available, the large individual variability in drug response results in only a modest reduction of the cardiovascular risk and unsatisfactory control of blood pressure in the hypertensive population as a whole. Two mechanisms, among others, are associated with essential hypertension and related organ damage: mutant α-adducin variants and high concentrations of endogenous ouabain. An antihypertensive agent, rostafuroxin, selectively inhibits these mechanisms in rodents. We investigated the molecular and functional effects of mutant α-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and cell-free systems and demonstrated that both mutant α-adducin variants and the ouabain-Na,K-ATPase (Na(+)- and K(+)-dependent adenosine triphosphatase) complex can interact with the Src-SH2 (Src homology 2) domain, increasing Src activity and the Src-dependent Na,K-ATPase phosphorylation and activity. Wild-type α-adducin or Na,K-ATPase in the absence of ouabain showed no interaction with the Src-SH2 domain. Rostafuroxin disrupted the interactions between the Src-SH2 domain and mutant α-adducin or the ouabain-Na,K-ATPase complex and blunted Src activation and Na,K-ATPase phosphorylation, resulting in blood pressure normalization in the hypertensive rats. We have also shown the translatability of these data to humans in a pharmacogenomic clinical trial, as described in the companion paper.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Ferrandi M,Molinari I,Torielli L,Padoani G,Salardi S,Rastaldi MP,Ferrari P,Bianchi G

doi

10.1126/scitranslmed.3001815

subject

Has Abstract

pub_date

2010-11-24 00:00:00

pages

59ra86

issue

59

eissn

1946-6234

issn

1946-6242

pii

2/59/59ra86

journal_volume

2

pub_type

杂志文章

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