Source:http://linkedlifedata.com/resource/pubmed/id/21106940
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
59
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| pubmed:dateCreated |
2010-11-25
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| pubmed:abstractText |
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 ?-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 ?-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and cell-free systems and demonstrated that both mutant ?-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 ?-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 ?-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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/17-(3-furyl)-5beta-androstane-3,14,1...,
http://linkedlifedata.com/resource/pubmed/chemical/Androstanols,
http://linkedlifedata.com/resource/pubmed/chemical/Antihypertensive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Calmodulin-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mutant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ouabain,
http://linkedlifedata.com/resource/pubmed/chemical/Sodium-Potassium-Exchanging ATPase,
http://linkedlifedata.com/resource/pubmed/chemical/adducin,
http://linkedlifedata.com/resource/pubmed/chemical/src-Family Kinases
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| pubmed:status |
MEDLINE
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| pubmed:month |
Nov
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| pubmed:issn |
1946-6242
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:day |
24
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| pubmed:volume |
2
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
59ra86
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| pubmed:meshHeading |
pubmed-meshheading:21106940-Androstanols,
pubmed-meshheading:21106940-Animals,
pubmed-meshheading:21106940-Antihypertensive Agents,
pubmed-meshheading:21106940-Blood Pressure,
pubmed-meshheading:21106940-Calmodulin-Binding Proteins,
pubmed-meshheading:21106940-Cell Line,
pubmed-meshheading:21106940-Cell-Free System,
pubmed-meshheading:21106940-Enzyme Activation,
pubmed-meshheading:21106940-Fluorescent Antibody Technique,
pubmed-meshheading:21106940-Humans,
pubmed-meshheading:21106940-Kidney,
pubmed-meshheading:21106940-Male,
pubmed-meshheading:21106940-Mutant Proteins,
pubmed-meshheading:21106940-Ouabain,
pubmed-meshheading:21106940-Protein Binding,
pubmed-meshheading:21106940-Protein Transport,
pubmed-meshheading:21106940-Rats,
pubmed-meshheading:21106940-Rats, Sprague-Dawley,
pubmed-meshheading:21106940-Signal Transduction,
pubmed-meshheading:21106940-Sodium-Potassium-Exchanging ATPase,
pubmed-meshheading:21106940-Transfection,
pubmed-meshheading:21106940-src Homology Domains,
pubmed-meshheading:21106940-src-Family Kinases
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| pubmed:year |
2010
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| pubmed:articleTitle |
Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 1: experimental studies.
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| pubmed:affiliation |
Prassis sigma-tau Research Institute, Settimo Milanese, Milan 20019, Italy.
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| pubmed:publicationType |
Journal Article
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