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Cardiovascular Research Advance Access originally published online on January 24, 2008
Cardiovascular Research 2008 78(3):440-448; doi:10.1093/cvr/cvn014
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
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Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKC{zeta} in the pulmonary artery adventitia

Mita Das*, Nana Burns, Shelly J. Wilson, Wojciech M. Zawada and Kurt R. Stenmark

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) {zeta} is a replication repressor of normal adventitial fibroblasts, we hypothesized that loss of the repressor activity of PKC{zeta} 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{zeta} in hypoxia-induced vascular adventitial remodelling, expression and activation of PKC{zeta} were also examined in lung sections of Fib-C and Fib-H animals by immunoperoxidase staining. Although constitutively active PKC{zeta} expression attenuated DNA synthesis in Fib-C, it stimulated proliferation in Fib-H. PKC{zeta}-specific myristoylated pseudosubstrate peptide inhibitor (PKC{zeta}-PI) induced replication in Fib-C, whereas the inhibitor blocked DNA synthesis in Fib-H. Hypoxia stimulated PKC{zeta} 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{zeta}-regulated mechanisms in hypoxia-exposed Fib-H. PKC{zeta} was selectively activated in the adventitial cells of the remodelled vascular wall, as demonstrated by strong immunoreactivity against the anti-phosphoPKC{zeta} antibody in the Fib-H lung sections.

Conclusion: PKC{zeta} 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{zeta} in the PA adventitia.

KEYWORDS Hypoxia; Pulmonary hypertension; Fibroblast proliferation; PKC{zeta}

Time for primary review: 35 days


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