title: Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension.
abstract: 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-kappaB 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-kappaB activation. Hemodynamic data, the expression of inhibitory (I)-kappaBalpha, caveolin-1, and Tie2 (a membrane protein), activation of PY-STAT3 and NF-kappaB, 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-kappaBalpha expression was present at 2 and 4 wk post-MCT. Superoxide chemiluminescence and NF-kappaB 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-kappaBalpha expression and reduced superoxide chemiluminescence at 2 wk but did not inhibit NF-kappaB activation despite attenuation of PAH. PDTC had no effect on established PAH. Increased superoxide chemiluminescence and NF-kappaB 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.
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Pawel M
authors.initials: PM
authors.lastname: Kaminski
authors.forename: John G
authors.initials: JG
authors.lastname: Edwards
authors.forename: Albert
authors.initials: A
authors.lastname: Yeh
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.forename: William H
authors.initials: WH
authors.lastname: Frishman
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gewitz
authors.forename: Rajamma
authors.initials: R
authors.lastname: Mathew
mesh_terms: D000166:Acridines / Q000378:metabolism; D000818:Animals; D051242:Caveolin 1 / Q000096:biosynthesis; D002462:Cell Membrane / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000648:ultrastructure; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced; D020672:I-kappa B Proteins / Q000096:biosynthesis; D008163:Luminescent Measurements; D008297:Male; D016686:Monocrotaline; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D013481:Superoxides / Q000378:metabolism; D013859:Thiocarbamates / Q000627:therapeutic use*
chemical_list: D000166:Acridines; C495537:Cav1 protein, rat; D051242:Caveolin 1; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D011759:Pyrrolidines; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D013859:Thiocarbamates; D013481:Superoxides; D000072000:NF-KappaB Inhibitor alpha; C033472:10,10'-dimethyl-9,9'-biacridinium; C020972:pyrrolidine dithiocarbamic acid; D016686:Monocrotaline; D042787:Receptor, TIE-2