Hydrogen sulfide mediates cardioprotection through Nrf2 signaling.
BACKGROUND
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.


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.
Calvert
John W
JW
Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, 550 Peachtree St NE, Atlanta, GA 30308, USA.
Jha
Saurabh
S
Gundewar
Susheel
S
Elrod
John W
JW
Ramachandran
Arun
A
Pattillo
Christopher B
CB
Kevil
Christopher G
CG
Lefer
David J
DJ
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000393:Air Pollutants / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D013879:Thioredoxins / Q000096:biosynthesis; D013997:Time Factors; D019210:Troponin I / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
D000393:Air Pollutants; C494820:Bad protein, mouse; C494812:Bcl2l1 protein, mouse; D002316:Cardiotonic Agents; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019210:Troponin I; C515559:Txn1 protein, mouse; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D013879:Thioredoxins; D051547:Heme Oxygenase-1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C081975:protein kinase C eta; D011493:Protein Kinase C; D006862:Hydrogen Sulfide