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Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 24, 2008
Cardiovascular Research, 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

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, W. Michael Zawada and Kurt R. Stenmark

Department of Pediatrics, University of Colorado Denver, Denver, CO 80262

Correspondence: Mita Das, Ph.D., Department of Pediatrics, B131, University of Colorado Denver, 4200 E. 9th Ave, Denver, CO 80262, Phone: 303-315-1194, Fax: 303-315-8353, Email: Mita.Das{at}uchsc.edu

Aims: Cultured fibroblasts of hypoxia-stimulated remodeled pulmonary artery (PA) adventitia proliferate at a greater rate compared to 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 remodeled PA.

Methods: 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 remodeling, expression and activation of PKC{zeta} were also examined in lung sections of Fib-C and Fib-H animals by immunoperoxidase staining.

Results: While constitutively active PKC{zeta} (CAPKC{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 remodeled vascular wall, as demonstrated by strong immunoreactivity against the anti-phosphoPKC{zeta} antibody in the Fib-H lung sections.

Conclusions: 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.

Time for primary review: 35


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