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Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKCζ in the pulmonary artery adventitia

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Mita Das, Nana Burns, Shelly J. Wilson, Wojciech M. Zawada, Kurt R. Stenmark
DOI: http://dx.doi.org/10.1093/cvr/cvn014 440-448 First published online: 24 January 2008

Abstract

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

Conclusion PKCζ 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 PKCζ in the PA adventitia.

  • Hypoxia
  • Pulmonary hypertension
  • Fibroblast proliferation
  • PKCζ
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