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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/L1250    most recent 00069.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Huang, J. Articles by Mathew, R. PubMed PubMed Citation Articles by Huang, J. Articles by Mathew, R.

Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension

Departments of ¹Pediatrics, ²Physiology, ³Pathology, and ⁴Medicine, New York Medical College, Valhalla, New York

Submitted 20 February 2007 ; accepted in final form 1 April 2008

Monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) in rats is preceded by an inflammatory response, progressive endothelial cell membrane disruption, reduction in the expression of caveolin-1, and reciprocal activation of STAT3 (PY-STAT3). Superoxide and NF-B have been implicated in PAH. To evaluate the role of caveolin-1, PY-STAT3 activation, and superoxide in PAH, MCT-injected rats were treated daily with pyrrolidine dithiocarbamate (PDTC; starting on days 1, 3, and 14 x 2 wk), an inhibitor of inflammation and NF-B activation. Hemodynamic data, the expression of inhibitory (I)-B, caveolin-1, and Tie2 (a membrane protein), activation of PY-STAT3 and NF-B, and superoxide chemiluminescence were examined. Rats developed progressive PAH at 2 wk post-MCT. There was progressive reduction in the expression of caveolin-1, Tie2, and activation of PY-STAT3 in the lungs. Reduction in I-B expression was present at 2 and 4 wk post-MCT. Superoxide chemiluminescence and NF-B activation were observed only at 2 wk post-MCT and both decreased by 4 wk post-MCT despite progressive PAH. PDTC (starting on days 1 and 3) rescued caveolin-1 and Tie2, reversed MCT-induced PY-STAT3 activation, and attenuated PAH. In addition, PDTC restored I-B expression and reduced superoxide chemiluminescence at 2 wk but did not inhibit NF-B activation despite attenuation of PAH. PDTC had no effect on established PAH. Increased superoxide chemiluminescence and NF-B activation appear to be a transient phenomenon in the MCT model. Thus the disruption of endothelial cell membrane integrity resulting in caveolin-1 loss and reciprocal activation of PY-STAT3 plays a key role in the MCT-induced PAH.

caveolin-1; inhibitory B; inflammation; PY-STAT3; Tie2