Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 1

Experimental studies

Mara Ferrandi, Isabella Molinari, Lucia Torielli, Gloria Padoani, Sergio Salardi, Maria Pia Rastaldi, Patrizia Ferrari, Giuseppe Bianchi

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish
Article number59ra86
JournalScience Translational Medicine
Volume2
Issue number59
DOIs
Publication statusPublished - Nov 24 2010

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Ouabain
Antihypertensive Agents
src Homology Domains
Genes
Phosphorylation
Blood Pressure
Proton-Translocating ATPases
Cell-Free System
Pharmacogenetics
Risk Reduction Behavior
Molecular Biology
Rodentia
adducin
rostafuroxin
sodium-translocating ATPase
Clinical Trials
Pharmaceutical Preparations
Population
Essential Hypertension

ASJC Scopus subject areas

  • Medicine(all)

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Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 1 : Experimental studies. / Ferrandi, Mara; Molinari, Isabella; Torielli, Lucia; Padoani, Gloria; Salardi, Sergio; Rastaldi, Maria Pia; Ferrari, Patrizia; Bianchi, Giuseppe.

In: Science Translational Medicine, Vol. 2, No. 59, 59ra86, 24.11.2010.

Research output: Contribution to journalArticle

Ferrandi, Mara ; Molinari, Isabella ; Torielli, Lucia ; Padoani, Gloria ; Salardi, Sergio ; Rastaldi, Maria Pia ; Ferrari, Patrizia ; Bianchi, Giuseppe. / Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 1 : Experimental studies. In: Science Translational Medicine. 2010 ; Vol. 2, No. 59.
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