Science translational medicine, 2010-11, Vol.2 (59), p.59ra86
2010
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- Autor(en) / Beteiligte
- Titel
- Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 1: experimental studies
- Ist Teil von
- Science translational medicine, 2010-11, Vol.2 (59), p.59ra86
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1946-6234eISSN: 1946-6242DOI: 10.1126/scitranslmed.3001815Titel-ID: cdi_pubmed_primary_21106940
- Format
- –
- Schlagworte
- Androstanols - pharmacology, Animals, Antihypertensive Agents - pharmacology, Blood Pressure - drug effects, Calmodulin-Binding Proteins - genetics, Calmodulin-Binding Proteins - metabolism, Cell Line, Cell-Free System, Enzyme Activation - drug effects, Fluorescent Antibody Technique, Humans, Kidney - drug effects, Kidney - pathology, Kidney - physiopathology, Male, Mutant Proteins - metabolism, Ouabain - pharmacology, Protein Binding - drug effects, Protein Transport - drug effects, Rats, Rats, Sprague-Dawley, Signal Transduction - drug effects, Sodium-Potassium-Exchanging ATPase - metabolism, src Homology Domains, src-Family Kinases - chemistry, src-Family Kinases - metabolism, Transfection