Linked Life Data

15375007

Source:http://linkedlifedata.com/resource/pubmed/id/15375007

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2004-10-15
pubmed:abstractText
The pulmonary arteries (PA) in pulmonary arterial hypertension (PAH) are constricted and remodeled;. They have suppressed apoptosis, partly attributable to suppression of the bone morphogenetic protein axis and selective downregulation of PA smooth muscle cell (PASMC) voltage-gated K+ channels, including Kv1.5. The Kv downregulation-induced increase in [K+]i, tonically inhibits caspases, further suppressing apoptosis. Mitochondria control apoptosis and produce activated oxygen species like H2O2, which regulate vascular tone by activating K+ channels, but their role in PAH is unknown. We show that dichloroacetate (DCA), a metabolic modulator that increases mitochondrial oxidative phosphorylation, prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality. Compared with MCT-PAH, DCA-treated rats (80 mg/kg per day in drinking water on day 14 after MCT, studied on day 21) have decreased pulmonary, but not systemic, vascular resistance (63% decrease, P<0.002), PA medial thickness (28% decrease, P<0.0001), and right ventricular hypertrophy (34% decrease, P<0.001). DCA is similarly effective when given at day 1 or day 21 after MCT (studied day 28) but has no effect on normal rats. DCA depolarizes MCT-PAH PASMC mitochondria and causes release of H2O2 and cytochrome c, inducing a 10-fold increase in apoptosis within the PA media (TUNEL and caspase 3 activity) and decreasing proliferation (proliferating-cell nuclear antigen and BrdU assays). Immunoblots, immunohistochemistry, laser-captured microdissection-quantitative reverse-transcription polymerase chain reaction and patch-clamping show that DCA reverses the Kv1.5 downregulation in resistance PAs. In summary, DCA reverses PA remodeling by increasing the mitochondria-dependent apoptosis/proliferation ratio and upregulating Kv1.5 in the media. We identify mitochondria-dependent apoptosis as a potential target for therapy and DCA as an effective and selective treatment for PAH.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1524-4571
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
95
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
830-40
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:15375007-Animals, pubmed-meshheading:15375007-Apoptosis, pubmed-meshheading:15375007-Cell Division, pubmed-meshheading:15375007-Cells, Cultured, pubmed-meshheading:15375007-Dichloroacetate, pubmed-meshheading:15375007-Drug Evaluation, Preclinical, pubmed-meshheading:15375007-Gene Expression Regulation, pubmed-meshheading:15375007-Heart Failure, pubmed-meshheading:15375007-Hemodynamics, pubmed-meshheading:15375007-Hypertension, Pulmonary, pubmed-meshheading:15375007-Hypertrophy, Right Ventricular, pubmed-meshheading:15375007-Kv1.5 Potassium Channel, pubmed-meshheading:15375007-Mitochondria, pubmed-meshheading:15375007-Monocrotaline, pubmed-meshheading:15375007-Muscle, Smooth, Vascular, pubmed-meshheading:15375007-Myocytes, Smooth Muscle, pubmed-meshheading:15375007-Organ Specificity, pubmed-meshheading:15375007-Oxidative Phosphorylation, pubmed-meshheading:15375007-Potassium Channels, Voltage-Gated, pubmed-meshheading:15375007-Pulmonary Artery, pubmed-meshheading:15375007-Rats, pubmed-meshheading:15375007-Shab Potassium Channels, pubmed-meshheading:15375007-Vascular Resistance
pubmed:year
2004
pubmed:articleTitle
Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis.
pubmed:affiliation
Department of Medicine and Pediatrics, University of Alberta, Edmonton, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't