Therapeutic metabolic inhibition: hydrogen sulfide significantly mitigates skeletal muscle ischemia reperfusion injury in vitro and in vivo.
BACKGROUND
Recent evidence suggests that hydrogen sulfide is capable of mitigating the degree of cellular damage associated with ischemia-reperfusion injury. The purpose of this study was to determine whether it is protective in skeletal muscle.


METHODS
This study used both in vitro (cultured myotubes subjected to sequential anoxia and normoxia) and in vivo (mouse hind-limb ischemia followed by reperfusion) models in which hydrogen sulfide (0 to 1000 μM) was delivered before the onset of oxygen deficiency. Injury score and apoptotic index were determined by analysis of specimens stained with hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, respectively.


RESULTS
In vitro, hydrogen sulfide reduced the apoptotic index by as much as 99 percent (p=0.001), with optimal protection conferred by raising intravascular hydrogen sulfide to 10 μM. In vivo, 10 μM hydrogen sulfide delivered before 3 hours of hind-limb ischemia followed by 3 hours of reperfusion resulted in protection against ischemia-reperfusion injury-induced cellular changes, as evidenced by significant decreases in injury score and apoptotic index (by as much as 91 percent; p=0.001). These findings were consistent at 4 weeks after injury and reperfusion.


CONCLUSIONS
These findings confirm that the preischemic delivery of hydrogen sulfide limits ischemia-reperfusion injury-induced cellular damage in myotubes and skeletal muscle and suggests that, when given in the appropriate dose, this molecule may have significant therapeutic applications in multiple clinical scenarios.
New York, N.Y. From the Laboratory for Bioregenerative Medicine and Surgery, Department of Surgery, Weill Cornell Medical College.
Peter W
PW
Henderson
Sunil P
SP
Singh
Andrew L
AL
Weinstein
Vijay
V
Nagineni
Daniel C
DC
Rafii
Daniel
D
Kadouch
David D
DD
Krijgh
Jason A
JA
Spector
D000280:Administration, Inhalation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006862:Hydrogen Sulfide / Q000008:administration & dosage / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects* / Q000473:pathology; D011292:Premedication; D015427:Reperfusion Injury / Q000517:prevention & control*; D014022:Tissue Survival / Q000187:drug effects
D006862:Hydrogen Sulfide