Document Detail


Redox-dependent coronary metabolic dilation.
MedLine Citation:
PMID:  17965288     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have observed that hydrogen peroxide (H2O2), the dismutated product of superoxide, is a coronary metabolic dilator and couples myocardial oxygen consumption to coronary blood flow. Because the chemical activity of H2O2 favors its role as an oxidant, and thiol groups are susceptible to oxidation, we hypothesized that coronary metabolic dilation occurs via a redox mechanism involving thiol oxidation. To test this hypothesis, we studied the mechanisms of dilation of isolated coronary arterioles to metabolites released by metabolically active (paced at 400 min) isolated cardiac myocytes and directly compared these responses with authentic H2O2. Studies were performed under control conditions and using interventions designed to reduce oxidized thiols [0.1 microM dithiothreitol (DTT) and 10 mM N-acetyl-L-cysteine (NAC)]. Aliquots of the conditioned buffer from paced myocytes produced vasodilation of isolated arterioles (peak response, 71% +/- 6% of maximal dilation), whereas H2O2 produced complete dilation (92% +/- 7%). Dilation to either the conditioned buffer or to H2O2 was significantly reduced by the administration of either NAC or DTT. The location of the thiols oxidized by the conditioned buffer or of H2O2 was determined by the administration of the fluorochromes monochlorobimane (20 microM) or monobromotrimethylammoniobimane (20 microM), which covalently label the reduced total or extracellular-reduced thiols, respectively. H2O2 or the conditioned buffer predominantly oxidized intracellular thiols since the fluorescent signal from monochlorobimane was reduced more than that of monobromotrimethylammoniobimane. To determine whether one of the intracellular targets of thiol oxidation that leads to dilation is the redox-sensitive kinase p38 mitogen-activated protein (MAP) kinase, we evaluated dilation following the administration of the p38 inhibitor SB-203580 (10 microM). The inhibition of p38 attenuated dilation to either H2O2 or to the conditioned buffer from stimulated myocytes by a similar degree, but SB-203580 did not attenuate dilation to nitroprusside. Western blot analysis for the activated form of p38 (phospho-p38) in the isolated aortae revealed robust activation of this enzyme by H2O2. Taken together, our results show that an active component of cardiac metabolic dilation, like that of H2O2, produces dilation by the oxidation of thiols, which are predominantly intracellular and dependent activation on the p38 MAP kinase. Thus coronary metabolic dilation appears to be mediated by redox-dependent signals.
Authors:
Shu-ichi Saitoh; Takahiko Kiyooka; Petra Rocic; Paul A Rogers; Cuihua Zhang; Albert Swafford; Gregory M Dick; Chandrasekar Viswanathan; Yoonjung Park; William M Chilian
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-10-26
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  293     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-12-06     Completed Date:  2008-01-31     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H3720-5     Citation Subset:  IM    
Affiliation:
Department of Integrative Medical Sciences, Northeastern Ohio University College of Medicine, 4209 State Rte. 44, Rootstown, OH 44272-0095, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetylcysteine / pharmacology
Animals
Antioxidants / pharmacology
Coronary Vessels / drug effects,  enzymology,  metabolism*
Culture Media, Conditioned / metabolism
Dithiothreitol / pharmacology
Enzyme Activation
Hydrogen Peroxide / metabolism
Imidazoles / pharmacology
Microscopy, Fluorescence
Myocytes, Cardiac / drug effects,  metabolism*
Nitroprusside / pharmacology
Oxidation-Reduction
Paracrine Communication*
Phosphorylation
Protein Kinase Inhibitors / pharmacology
Pyridines / pharmacology
Rats
Rats, Wistar
Reactive Oxygen Species / metabolism*
Reducing Agents / pharmacology
Sulfhydryl Compounds / metabolism*
Vasodilation* / drug effects
Vasodilator Agents / pharmacology
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  metabolism
Grant Support
ID/Acronym/Agency:
HL 32788/HL/NHLBI NIH HHS; HL 73755/HL/NHLBI NIH HHS; HL 77566/HL/NHLBI NIH HHS; HL 85119/HL/NHLBI NIH HHS; RR 018766/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Culture Media, Conditioned; 0/Imidazoles; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/Reactive Oxygen Species; 0/Reducing Agents; 0/SB 203580; 0/Sulfhydryl Compounds; 0/Vasodilator Agents; 15078-28-1/Nitroprusside; 3483-12-3/Dithiothreitol; 616-91-1/Acetylcysteine; 7722-84-1/Hydrogen Peroxide; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

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