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Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C.

Abstract
Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-alpha and IL-1beta via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-alpha and IL-1beta mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-alpha and IL-1beta mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application.
AuthorsBen M Tsai, Meijing Wang, Jeffrey M Pitcher, Kirstan K Meldrum, Daniel R Meldrum
JournalAmerican journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 287 Issue 6 Pg. L1215-9 (Dec 2004) ISSN: 1040-0605 [Print] United States
PMID15321786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Alkaloids
  • Benzophenanthridines
  • Cytokines
  • Enzyme Inhibitors
  • Phenanthridines
  • chelerythrine
  • Protein Kinase C
Topics
  • Alkaloids
  • Animals
  • Benzophenanthridines
  • Cell Hypoxia (physiology)
  • Cytokines (genetics)
  • Enzyme Inhibitors (pharmacology)
  • In Vitro Techniques
  • Muscle Contraction (drug effects, physiology)
  • Muscle, Smooth, Vascular (physiology)
  • Phenanthridines (pharmacology)
  • Protein Kinase C (metabolism)
  • Pulmonary Artery (physiology)
  • Rats
  • Vasoconstriction (drug effects, physiology)

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