Deficient BH^sub 4^ production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes

Adult rat cardiac myocytes typically display a phenotypic response to cytokines manifested by low or no increases in nitric oxide (NO) production via inducible NO synthase (iNOS) that distinguishes them from other cell types. To better characterize this response, we examined the expression of tetrah...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2008-11, Vol.295 (5), p.H2178
Main Authors: Ionova, Irina A, Vásquez-Vivar, Jeannette, Whitsett, Jennifer, Herrnreiter, Anja, Medhora, Meetha, Cooley, Brian C, Pieper, Galen M
Format: Article
Language:English
Subjects:
Cells
Cytokines
Nitric oxide
Proteins
Rodents
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Summary:Adult rat cardiac myocytes typically display a phenotypic response to cytokines manifested by low or no increases in nitric oxide (NO) production via inducible NO synthase (iNOS) that distinguishes them from other cell types. To better characterize this response, we examined the expression of tetrahydrobiopterin (BH...)-synthesizing and arginine-utilizing genes in cytokine-stimulated adult cardiac myocytes. Intracellular BH... and 7,8-dihydrobiopterin (BH...) and NO production were quantified. Cytokines induced GTP cyclohydrolase and its feedback regulatory protein but with deficient levels of BH4 synthesis. Despite the induction of iNOS protein, cytokine-stimulated adult cardiac myocytes produced little or no increase in NO versus unstimulated cells. Western blot analysis under nonreducing conditions revealed the presence of iNOS monomers. Supplementation with sepiapterin (a precursor of BH...) increased BH... as well as BH..., but this did not enhance NO levels or eliminate iNOS monomers. Similar findings were confirmed in vivo after treatment of rat cardiac allograft recipients with sepiapterin. It was found that expression of dihydrofolate reductase, required for full activity of the salvage pathway, was not detected in adult cardiac myocytes. Thus, adult cardiac myocytes have a limited capacity to synthesize BH... after cytokine stimulation. The mechanisms involve posttranslational factors impairing de novo and salvage pathways. These conditions are unable to support active iNOS protein dimers necessary for NO production. These findings raise significant new questions about the prevailing understanding of how cytokines, via iNOS, cause cardiac dysfunction and injury in vivo during cardiac inflammatory disease states since cardiac myocytes are not a major source of high NO production. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0363-6135
1522-1539