Linked Life Data

19679640

Source:http://linkedlifedata.com/resource/pubmed/id/19679640

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2009-12-1
pubmed:abstractText
Voltage-gated potassium (Kv)1.5 is decreased in pulmonary arteries (PAs) of patients with idiopathic pulmonary arterial hypertension (IPAH) and in experimental models including mice with SM22alpha-targeted overexpression of the serotonin transporter (5-HTT). The mechanisms underlying these abnormalities, however, remain unknown. Dichloroacetate (DCA) inhibits chronic hypoxia- or monocrotaline-induced PAH by inhibiting nuclear factor of activated T-cells (NFAT)c2 and increasing Kv1.5. Therefore, we hypothesized that DCA could regress established PAH in SM22-5-HTT+ mice. We evaluated pulmonary hemodynamics, vascular remodeling, NFATc2, and Kv1.5 protein in 20-wk-old SM22-5-HTT+ or wild-type mice treated for 1, 7, and 21 d with DCA, cyclosporine-A (NFAT inhibitor), or vehicle. DCA partially reversed PAH in SM22-5-HTT+ mice by decreasing proliferation and increasing apoptosis in muscularized PAs. Furthermore, serotonin (10(-8)-10(-6) M) dose-dependently increased PA-smooth muscle cell (PA-SMC) proliferation in culture (EC(50)=0.97 x 10(-7) M) and DCA (5 x 10(-4) M) vs. PBS markedly reduced the growth of PA-SMC from IPAH and control patients treated with the highest dose of serotonin by 50 and 30%, respectively. Finally, although serotonin induces NFATc2 activation in PA-SMCs, inhibition of NFATc2 alone with cyclosporine-A was not sufficient for reversing PAH in this model. Our results support the possibility that DCA may be an interesting agent for investigation in patients with PAH.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1530-6860
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
23
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4135-47
pubmed:meshHeading
pubmed-meshheading:19679640-Animals, pubmed-meshheading:19679640-Apoptosis, pubmed-meshheading:19679640-Cell Proliferation, pubmed-meshheading:19679640-Cells, Cultured, pubmed-meshheading:19679640-Dichloroacetate, pubmed-meshheading:19679640-Female, pubmed-meshheading:19679640-Fluoxetine, pubmed-meshheading:19679640-Gene Expression Regulation, pubmed-meshheading:19679640-Hypertension, Pulmonary, pubmed-meshheading:19679640-Kv1.5 Potassium Channel, pubmed-meshheading:19679640-Male, pubmed-meshheading:19679640-Mice, pubmed-meshheading:19679640-Microfilament Proteins, pubmed-meshheading:19679640-Muscle, Smooth, Vascular, pubmed-meshheading:19679640-Muscle Proteins, pubmed-meshheading:19679640-Myocytes, Smooth Muscle, pubmed-meshheading:19679640-NFATC Transcription Factors, pubmed-meshheading:19679640-Pulmonary Artery, pubmed-meshheading:19679640-Serotonin Plasma Membrane Transport Proteins, pubmed-meshheading:19679640-Serotonin Uptake Inhibitors
pubmed:year
2009
pubmed:articleTitle
Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter.
pubmed:affiliation
INSERM Unity "Pulmonary Hypertension: Pathophysiology and Innovative Therapies," Centre Chirurgical Marie Lannelongue, 133 Avenue de la Résistance, 92350 Le Plessis-Robinson, France. christophe.guignabert@inserm.fr
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't