Conference: 2008 International PHA Conference and Scientific Sessions
Release Date: 06.20.2008
Presentation Type: Abstracts
Mathew R., Huang J., Olson S., Gewitz M.
New York Medical College, Valhalla, NY, USA
BACKGROUND: We have previously shown that monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) is associated with progressive upregulation of IL-6 mRNA, loss of caveolin-1 and activation of PY-STAT3, a proproliferative transcription factor in the lungs. PY-STAT3 is activated by IL-6 and growth factors, and is suppressed by caveolin-1. Recent studies show PY-STAT3 activation in pulmonary artery endothelial cells (PAEC) isolated from patients with idiopathic PAH. Based on these observations we hypothesized that PY-STAT3 may have a pivotal role in the pathogenesis of PAH.
METHODS: To investigate the role of PY-STAT3 in PAH:
- we treated the MCT-injected rats with pyrrolidine dithiocarbamate (PDTC x14 days), an inhibitor of inflammation and of NF-kB activation. Hemodynamic data, expression of caveolin-1, IkB a, activation of PY-STAT3 and of NF-kB were examined at 48h, 1 and 2 wks post-MCT and compared with controls.
- We subjected rats to hypobaric hypoxia (50% Kpa) and studied at 48h, 1 and 2 wks of hypoxia. Hemodynamic data, expression of caveolin-1, eNOS and PY-STAT3 activation were examined.
- Since PY-STAT3 activation was found predominantly in the endothelial cells, we exposed bovine PAEC to hypoxia (5% O2) for 24 hrs and examined the expression of the molecules of interest
- The PDTC treatment not only rescued MCT-induced loss of caveolin-1 but also inhibited PY-STAT3 activation and attenuated PAH. NF-kB activation was a transient phenomenon in this model.
- Hypoxia-induced PAH was associated with progressive activation of PY-STAT3 without alterations in the expression of caveolin-1. There was a slight but significant increase in eNOS expression at 1 wk of hypoxia.
- Within 24 hr of hypoxia PAEC showed tight caveolin-1 and eNOS complex formation with its translocation to cytoplasm with concomitant activation of PY-STAT3.
COMMENTS AND CONCLUSIONS:
- MCT–induced loss of caveolin-1 results in PY-STAT3 activation. The rescue of caveolin-1 inhibits PY-STAT3 activation and attenuates PAH.
- Importantly, hypoxia-induced PAH exhibited progressive PY-STAT3 activation. Although caveolin-1 expression remained unaltered, hypoxia-induced caveolin-1/eNOS complex formation is likely to have rendered caveolin-1 dysfunctional resulting in PY-STAT3 activation. Thus, PY-STAT3 activation occurs in several models of PAH. Therefore, we conclude that PY-STAT3 is an upstream regulator in PAH.