Deficient BH4production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes
| Autor: | Meetha Medhora, Jeannette Vasquez-Vivar, Irina A. Ionova, Galen M. Pieper, Jennifer Whitsett, Anja Herrnreiter, Brian C. Cooley |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Sepiapterin Time Factors Physiology medicine.medical_treatment Nitric Oxide Synthase Type II Rats Inbred WF Biopterin Nitric Oxide Nitric oxide Rats Sprague-Dawley chemistry.chemical_compound Physiology (medical) Internal medicine medicine Animals Myocyte Myocytes Cardiac RNA Messenger GTP Cyclohydrolase Cells Cultured Regulation of gene expression Arginase biology Intracellular Signaling Peptides and Proteins Proteins Articles Tetrahydrobiopterin Pterins Rats Nitric oxide synthase Alcohol Oxidoreductases Tetrahydrofolate Dehydrogenase Endocrinology Cytokine chemistry Rats Inbred Lew biology.protein Cytokines Heart Transplantation Phosphorus-Oxygen Lyases Cardiology and Cardiovascular Medicine medicine.drug |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 295:H2178-H2187 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.00748.2008 |
| Popis: | 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 (BH4)-synthesizing and arginine-utilizing genes in cytokine-stimulated adult cardiac myocytes. Intracellular BH4and 7,8-dihydrobiopterin (BH2) and NO production were quantified. Cytokines induced GTP cyclohydrolase and its feedback regulatory protein but with deficient levels of BH4synthesis. 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 BH4) increased BH4as well as BH2, 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 BH4after 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. |
| Databáze: | OpenAIRE |
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