Conference: 2010 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Scientific Sessions
Mathew R, Huang J, Gewitz MH.
Section of Pediatric Cardiology, Maria Fareri Children's Hospital at Westchester Medical Center, New York Medical College, Valhalla, NY, USA
BACKGROUND. We have previously shown that monocrotaline (MCT)-induced pulmonary hypertension (PH) is associated with an early and progressive IL-6 mRNA upregulation, IL-6 bioactivity, loss of endothelial caveolin-1 and reciprocal PY-STAT3 activation. PY-STAT3 is activated by IL-6, and caveolin-1 suppresses PYSTAT3 activation. Caveolin-1, an important immunomodulator, inhibits cell proliferation and participates in apoptosis. Anti-inflammatory treatment instituted early inhibits IL-6 upregulation, rescues caveolin-1, inhibits PY-STAT3 activation and attenuates PH. Our main purpose was to investigate whether inflammation played any role in hypoxia-induced PH in rats and to compare and contrast with the MCT model.
METHODS. Male Sprague-Dawley rats (150-175 g) were subjected to hypobaric (1/2 atmospheric) hypoxia or given a single sc injection of MCT (60 mg/kg). Hemodynamic data, the expression of caveolin-1and PYSTAT3 in the lungs were examined at 48h, 1 and 2 wks.
RESULTS. PH and RVH were observed at 2 wks post-MCT and at 1and 2 wks of hypoxia. PY-STAT3 activation occurred in both models before the onset of PH and was progressive. The MCT model revealed progressive loss of caveolin-1; whereas in the hypoxia model, caveolin-1 expression was not altered.
CONCLUSIONS. MCT-induced PH is associated with disruption of endothelial caveolin-1 and reciprocal activation of PY-STAT3. In contrast, the hypoxia model exhibited PY-STAT3 activation without concomitant loss of caveolin-1. Importantly, these dissimilar models of PH show hyper-activation of PY-STAT3 before the onset of PH, indicating a role of inflammatory response to injury in the pathogenesis of PH. Since caveolin-1 suppresses PY-STAT3 activation; the significant PY-STAT3 activation in the hypoxia model may be indicative of caveolin-1 dysfunction. Thus, the disruption or dysfunction of endothelial caveolin-1 may promote inflammatory response and cell proliferation, contributing to PH.