Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 45, Issue 7, Pages 994-1001Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.06.017
Keywords
tetrahydrobiopterin; aconitase; nitric oxide; cytokines; lipopolysaccharide
Funding
- NCI NIH HHS [R01 CA077822, R01 CA077822-08] Funding Source: Medline
- NHLBI NIH HHS [R01 HL078937-03, R01 HL067244, R01 HL080468-03, R01 HL080468, HL067244, HL078937, R01 HL067244-06, R01 HL078937] Funding Source: Medline
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There is evidence that nitric oxide (NO) formation in adult cardiomyrocytes stimulated with lipopolysaccharide (LPS) is not commensurate with iNOS levels. Tetrahydrobiopterin (BH4) is a key factor in the stabilization and NO production by iNOS homodimer. Thus we hypothesized that BH4 is a limiting factor for NO production in adult cardiomyrocytes in response to LPS and cytokines (TNF-alpha, IL-1 IFN-gamma alone, or mixed). it was verified that I-PS and cytokines induced iNOS expression which did not translate into increased nitrite or [C-14]citrulline production. This response coincided with defective BH4 synthesis and low GTP cyclohydrolase activity. Furthermore, supplementation with BH4 and ascorbate failed to increase iNOS activity. This effect was related to preferential accumulation of BH2 rather than BH4 in these cells. Uncoupled iNOS activity in stimulated cells was examined Using mitochondrial aconitase activity as an endogenous marker of superoxide anion radical (O-2(-)) formation, and found not to be significantly inhibited. 2-Hydroxyethidium also was not significantly increased. We conclude that adult cardiomyocytes are an unlikely source of NO and O-2(-) in inflammatory conditions. This finding adds a new and unexpected layer of complexity to our, understanding of the responses of the adult heart to inflammation. (C) 2008 Elsevier Inc. All rights reserved.
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