Cardiovascular Research Advance Access first published online on January 24, 2008
This version [Corrected Proof] published online on February 22, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn014
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Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKC
in the pulmonary artery adventitia
Department of Pediatrics, B131, University of Colorado Denver, School of Medicine, 4200 E. 9th Avenue, Denver, CO 80262, USA
* Corresponding author. Tel: +1 303 315 1194; fax: +1 303 315 8353. E-mail address: mita.das{at}uchsc.edu
Aims: Cultured fibroblasts of hypoxia-stimulated remodelled pulmonary artery (PA) adventitia proliferate at a greater rate compared with those of normal adventitia. Since protein kinase C (PKC) 
is a replication repressor of normal adventitial fibroblasts, we hypothesized that loss of the repressor activity of PKC might contribute to increased rate of proliferation in adventitial cells of remodelled PA.
Methods and results: Isolated PA adventitial fibroblasts of neonatal control (Fib-C) and chronic hypoxia-exposed (Fib-H) calves were used to test our hypothesis. For evaluation of the role of PKC in hypoxia-induced vascular adventitial remodelling, expression and activation of PKC were also examined in lung sections of Fib-C and Fib-H animals by immunoperoxidase staining. Although constitutively active PKC expression attenuated DNA synthesis in Fib-C, it stimulated proliferation in Fib-H. PKC-specific myristoylated pseudosubstrate peptide inhibitor (PKC-PI) induced replication in Fib-C, whereas the inhibitor blocked DNA synthesis in Fib-H. Hypoxia stimulated PKC as well as MAP kinase kinase (MEK)1/2 and extracellular signal-regulated kinase (ERK)1/2 phosphorylation in Fib-H cells. However, ERK1/2 activation was mediated by both MEK1/2-dependent and MEK1/2-independent PKC-regulated mechanisms in hypoxia-exposed Fib-H. PKC was selectively activated in the adventitial cells of the remodelled vascular wall, as demonstrated by strong immunoreactivity against the anti-phosphoPKC antibody in the Fib-H lung sections.
Conclusion: PKC acts as a replication repressor in Fib-C cells; however, the same isozyme mediates Fib-H proliferation. Thus, chronic exposure to hypoxia leads to the emergence of cells lacking anti-replication activity of PKC in the PA adventitia.
KEYWORDS Hypoxia; Pulmonary hypertension; Fibroblast proliferation; PKC
Time for primary review: 35 days
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Cardiovasc Res 2008 78: 409-410.
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