Document Detail

Hydrogen sulfide mediates cardioprotection through Nrf2 signaling.
MedLine Citation:
PMID:  19608979     Owner:  NLM     Status:  MEDLINE    
RATIONALE: The recent emergence of hydrogen sulfide (H(2)S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms.
OBJECTIVE: The present study evaluated potential mechanisms of H(2)S-mediated cardioprotection using an in vivo model of pharmacological preconditioning.
METHODS AND RESULTS: H(2)S (100 microg/kg) or vehicle was administered to mice via an intravenous injection 24 hours before myocardial ischemia. Treated and untreated mice were then subjected to 45 minutes of myocardial ischemia followed by reperfusion for up to 24 hours, during which time the extent of myocardial infarction was evaluated, circulating troponin I levels were measured, and the degree of oxidative stress was evaluated. In separate studies, myocardial tissue was collected from treated and untreated mice during the early (30 minutes and 2 hours) and late (24 hours) preconditioning periods to evaluate potential cellular targets of H(2)S. Initial studies revealed that H(2)S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin I levels, and oxidative stress. During the early preconditioning period, H(2)S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants and increased the phosphorylation of protein kinase Cepsilon and STAT-3. During the late preconditioning period, H(2)S increased the expression of antioxidants (heme oxygenase-1 and thioredoxin 1), increased the expression of heat shock protein 90, heat shock protein 70, Bcl-2, Bcl-xL, and cyclooxygenase-2 and also inactivated the proapoptogen Bad.
CONCLUSIONS: These results reveal that the cardioprotective effects of H(2)S are mediated in large part by a combination of antioxidant and antiapoptotic signaling.
John W Calvert; Saurabh Jha; Susheel Gundewar; John W Elrod; Arun Ramachandran; Christopher B Pattillo; Christopher G Kevil; David J Lefer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-07-16
Journal Detail:
Title:  Circulation research     Volume:  105     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-14     Completed Date:  2009-09-22     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  365-74     Citation Subset:  IM    
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MeSH Terms
Active Transport, Cell Nucleus / drug effects
Air Pollutants / pharmacology
Cardiotonic Agents / pharmacology*
Cell Nucleus / metabolism*
Cyclooxygenase 2 / biosynthesis
Gene Expression Regulation / drug effects
HSP70 Heat-Shock Proteins / biosynthesis
HSP90 Heat-Shock Proteins / biosynthesis
Heme Oxygenase-1 / biosynthesis
Hydrogen Sulfide / pharmacology*
Mice, Inbred ICR
Mice, Knockout
Myocardial Infarction / metabolism,  prevention & control*
Myocardial Reperfusion Injury / metabolism,  prevention & control
NF-E2-Related Factor 2 / metabolism*
Oxidative Stress
Phosphorylation / drug effects
Protein Kinase C / metabolism
STAT3 Transcription Factor / biosynthesis
Signal Transduction / drug effects*
Thioredoxins / biosynthesis
Time Factors
Troponin I / metabolism
bcl-Associated Death Protein / biosynthesis
bcl-X Protein / biosynthesis
Grant Support
2 R01 HL-060849-09/HL/NHLBI NIH HHS; 5R01 HL-092141-01/HL/NHLBI NIH HHS; F32 DK 077380-01/DK/NIDDK NIH HHS; R01 HL060849/HL/NHLBI NIH HHS; R01 HL060849-09/HL/NHLBI NIH HHS; R01 HL092141/HL/NHLBI NIH HHS; R01 HL092141-01A1/HL/NHLBI NIH HHS; R01 HL093579/HL/NHLBI NIH HHS; R01 HL093579-01A1/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Air Pollutants; 0/Bad protein, mouse; 0/Bcl2l1 protein, mouse; 0/Cardiotonic Agents; 0/HSP70 Heat-Shock Proteins; 0/HSP90 Heat-Shock Proteins; 0/NF-E2-Related Factor 2; 0/Nfe2l2 protein, mouse; 0/STAT3 Transcription Factor; 0/Stat3 protein, mouse; 0/Troponin I; 0/Txn1 protein, mouse; 0/bcl-Associated Death Protein; 0/bcl-X Protein; 52500-60-4/Thioredoxins; EC 1.14.99.-/Ptgs2 protein, mouse; EC 2; EC Oxygenase-1; EC 2.7.1.-/protein kinase C eta; EC Kinase C; YY9FVM7NSN/Hydrogen Sulfide

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