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Caveolin‐1 rescue is associated with the inhibition of STAT3 activation and attenuation of pulmonary hypertension
Author(s) -
Mathew Rajamma,
Huang Jing,
Gewitz Michael
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1435-c
Subject(s) - caveolin 1 , stat3 , chemistry , cancer research , pulmonary hypertension , enos , microbiology and biotechnology , medicine , signal transduction , biology , biochemistry , nitric oxide , nitric oxide synthase
Monocrotaline (MCT)‐induced pulmonary hypertension (PH) is associated with a loss of caveolin‐1 (caveolar membrane protein) expression and reciprocal activation of STAT3 (PY‐STAT3), a proproliferative facotor. In several cell systems, loss of caveolin‐1 is associated with the activation of cell proliferative pathways, and reduction in the expression of p21 waf1/cip1 , a cyclin‐dependent kinase that blocks DNA replication. To assess the role of caveolin‐1 and PY‐STAT3 in PH, MCT‐injected rats were treated with molsidomine or pyrrolidine dithiocarbamate (PDTC). Two wks post‐MCT, rats exhibited significant PH and RVH. Pulmonary arteries in these rats revealed a significant reduction in the expression of cav‐1 and p21 waf1/cip1 , and activation of PY‐STAT3. Molsidomine and PDTC significantly attenuated MCT‐induced PH and RVH. This attenuation of PH was associated not only with the preservation of caveolin‐1 and p21 waf1/cip1 , but also inhibition of PY‐STAT3 activation. Furthermore, PECAM‐1 and Tie2 (caveolar membrane proteins) were also rescued indicating a generalized restoration of endothelial cell membrane integrity. We conclude that the restoration of caveolin‐1 led to inhibition of PY‐STAT3 activation and an increase in the expression of p21 waf1/cip1 , resulting in the inhibition of cell proliferation and attenuation of PH. Thus, caveolin‐1 and PY‐STAT3 play a pivotal role in pulmonary vascular health.