Thioredoxin 1 is essential for sodium sulfide-mediated cardioprotection in the setting of heart failure.
OBJECTIVE
The aim of this study was to determine whether thioredoxin 1 (Trx1) mediates the cardioprotective effects of hydrogen sulfide (H2S) in a model of ischemic-induced heart failure (HF).


RESULTS
Mice with a cardiac-specific overexpression of a dominant negative mutant of Trx1 and wild-type littermates were subjected to ischemic-induced HF. Treatment with H2S as sodium sulfide (Na2S) not only increased the gene and protein expression of Trx1 in the absence of ischemia but also augmented the HF-induced increase in both. Wild-type mice treated with Na2S experienced less left-ventricular dilatation, improved left-ventricular function, and less cardiac hypertrophy after the induction of HF. In contrast, Na2S therapy failed to improve any of these parameters in the dominant negative mutant of Trx1 mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S therapy inhibited HF-induced apoptosis signaling kinase-1 signaling and nuclear export of histone deacetylase 4 in a Trx1-dependent manner.


CONCLUSIONS
These findings provide novel information that the upregulation of Trx1 by Na2S therapy in the setting of HF sets into motion events, such as the inhibition of apoptosis signaling kinase-1 signaling and histone deacetylase 4 nuclear export, which ultimately leads to the attenuationof left-ventricular remodeling.
Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, 550 Peachtree St NE, Atlanta, GA 30308, USA.
Chad K
CK
Nicholson
Jonathan P
JP
Lambert
Jeffery D
JD
Molkentin
Junichi
J
Sadoshima
John W
JW
Calvert
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D017930:Genes, Reporter; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014463:Ultrasonography; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002316:Cardiotonic Agents; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D013440:Sulfides; C515559:Txn1 protein, mouse; D013879:Thioredoxins; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; C033479:sodium sulfide; D006862:Hydrogen Sulfide