Submitted on February 20, 2007
Accepted on April 1, 2008
Pyrrolidine Dithiocarbamate Restores Endothelial Cell Membrane Integrity and Attenuates Monocrotaline-Induced Pulmonary Artery Hypertension
Jing Huang1, Pawel M Kaminski2, John G. Edwards2, Albert Yeh3, Michael S. Wolin4, William H Frishman5, Michael H Gewitz6, and Rajamma Mathew1*
1 Pediatrics, New York Medical College, Valhalla, New York, United States
2 Physiology, New York Medical College, Valhalla, New York, United States
3 Pathology, New York medical College, Valhalla, New York, United States
4 Department of Physiology, New York Medical College, Valhalla, New York, United States
5 Medicine, New York Medical College, Valhalla , New York, United States
6 Pediatrics, New York Medical College, Valhalla , New York, United States
* To whom correspondence should be addressed. E-mail: rajamma_mathew{at}nymc.edu.
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 day 1, 3 and 14 x 2 wks) 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 wks post-MCT. There were 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 wks post-MCT. Superoxide chemiluminescence and NF-B activation were observed only at 2 wks post-MCT and both decreased by 4 wks post-MCT despite progressive PAH. PDTC (starting on day 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 wks, 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 cav-1 loss and reciprocal activation of PY-STAT3 plays a key role in the MCT-induced PAH.
