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Cardiovasc Res. 2008 Jun 1;78(3):440-8. doi: 10.1093/cvr/cvn014. Epub 2008 Jan 24.

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

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1
Department of Pediatrics, B131, University of Colorado Denver, School of Medicine, 4200 E. 9th Avenue, Denver, CO 80262, USA. mita.das@uchsc.edu

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

CONCLUSION:

PKCzeta 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 PKCzeta in the PA adventitia.

PMID:
18218684
DOI:
10.1093/cvr/cvn014
[Indexed for MEDLINE]
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