Characterization of Perceived Hyperoxia in Isolated Primary Cardiac Fibroblasts and in the Reoxygenated Heart

Sashwati Roy, Savita Khanna, William A. Wallace, Jani Lappalainen, Cameron Rink, Arturo J. Cardounel, Jay L. Zweier, Chandan K. Sen

Research output: Contribution to journalArticlepeer-review

Abstract

Under normoxic conditions, pO2 ranges from 90 to <3 torr in mammalian organs with the heart at ∼35 torr (5%) and arterial blood at ∼100 torr. Thus, "normoxia" for cells is an adjustable variable. In response to chronic moderate hypoxia, cells adjust their normoxia set point such that reoxygenation-dependent relative elevation of pO2 results in perceived hyperoxia. We hypothesized that O2, even in marginal relative excess of the pO2 to which cells are adjusted, results in the activation of specific O2-sensitive signal transduction pathways that alter cellular phenotype and function. Thus, reperfusion causes damage to the tissue at the focus of ischemia while triggering remodeling in the peri-infarct region by means of perceived hyperoxia. We reported first evidence demonstrating that perceived hyperoxia triggers the differentiation of cardiac fibroblasts (CF) to myofibroblasts by a p21-dependent mechanism (Roy, S., Khanna, S., Bickerstaff, A. A., Subramanian, S. V., Atalay, M., Bierl, M., Pendyala, S., Levy, D., Sharma, N., Venojarvi, M., Strauch, A., Orosz, C. G., and Sen, C. K. (2003) Circ. Res. 92, 264-271). Here, we sought to characterize the genomic response to perceived hyperoxia in CF using GeneChips™. Candidate genes were identified, confirmed and clustered. Cell cycle- and differentiation-associated genes represented a key target of perceived hyperoxia. Bioinformatics-assisted pathway reconstruction revealed the specific signaling processes that were sensitive to perceived hyperoxia. To test the significance of our in vitro findings, a survival model of rat heart focal ischemia-reperfusion (I-R) was investigated. A significant induction in p21 mRNA expression was observed in I-R tissue. The current results provide a comprehensive molecular definition of perceived hyperoxia in cultured CF. Furthermore, the first evidence demonstrating activation of perceived hyperoxia sensitive genes in the cardiac I-R tissue is presented.

Original languageEnglish (US)
Pages (from-to)47129-47135
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number47
DOIs
StatePublished - Nov 21 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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