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Author Notes:

To whom correspondence should be addressed. E-mail: dlefe1@lsuhsc.edu.

D.J.P., K.K., E.E.K., J.W.E., and D.J.L. designed research

A.L.K., D.J.P., S.B., H.O., K.K., C.K.N., K.N.I., Y.-X.T., T.R.D., E.E.K., and J.W.E. performed research

J.W.C., Y.-X.T., T.R.D., E.E.K., P.L.H., and R.W. contributed new reagents/analytic tools

A.L.K. and D.J.P. analyzed data

D.J.P., J.M.B., and D.J.L. wrote the paper

A.L.K. and D.J.P. contributed equally to this work.

We thank Valeria Hebert, Marah Condit, and Benjamin Predmore, as well as the University of Pittsburgh Center for Biological Imaging, for expert technical assistance.

D.J.L. is a participant in a pending US patent, filed through the National Institutes of Health (patent no. 60/511, 244), regarding the use of sodium nitrite in cardiovascular disease.

D.J.L. and J.W.E. are founders of and scientific advisors for Sulfagenix, a biotechnology company that is currently developing hydrogen sulfide-based therapeutics for human disease conditions.

The conflicts are considered significant.


Research Funding:

This work was supported by Grants from the National Heart, Lung, and Blood Institute (1R01 HL092141, 1R01 HL093579, 1U24 HL 094373, and 1P20 HL113452 to D.J.L., and 5R01 HL 098481 to J.W.C.).

These studies were also supported by the Canadian Institutes of Health Research (R.W.).

We are also grateful for the generous financial support from the Carlyle Fraser Heart Center of Emory University and the Louisiana State University Health Foundation in New Orleans.


  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • eNOS uncoupling
  • myocardial infarction
  • cystathionase
  • Cth
  • nitrite
  • AKT
  • H2S

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

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Journal Title:

Proceedings of the National Academy of Sciences


Volume 111, Number 8


, Pages 3182-3187

Type of Work:

Article | Final Publisher PDF


Previous studies have demonstrated that hydrogen sulfide (H 2 S) protects against multiple cardiovascular disease states in a similar manner as nitric oxide (NO). H 2 S therapy also has been shown to augment NO bioavailability and signaling. The purpose of this study was to investigate the impact of H 2 S deficiency on endothelial NO synthase (eNOS) function, NO production, and ischemia/reperfusion (I/R) injury. We found that mice lacking the H 2 S-producing enzyme cystathionine γ-lyase (CSE) exhibit elevated oxidative stress, dysfunctional eNOS, diminished NO levels, and exacerbated myocardial and hepatic I/R injury. In CSE KO mice, acute H 2 S therapy restored eNOS function and NO bioavailability and attenuated I/R injury. In addition, we found that H 2 S therapy fails to protect against I/R in eNOS phosphomutant mice (S1179A). Our results suggest that H 2 S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation.

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© 2014 National Academy of Sciences

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