Publications

 

Complete List of Published Work in MyBibliography

 

Contributions to Science

My early research efforts were focused on the investigation of the effects of cardiovascular diseases on endothelial dysfunction and we were among the first labs to demonstrate a profound reduction in endothelial-dependent vasorelaxation of coronary vessels following myocardial ischemia and reperfusion. Our central hypothesis in these experiments was that the loss of coronary endothelial function and nitric oxide (NO) production contributed to myocardial cell death and lead to the concept that NO based therapies could attenuate myocardial reperfusion injury. We demonstrated that increased oxidative stress occurring upon reperfusion of the ischemic myocardium resulted in attenuated coronary vascular reactivity that was abrogated by antioxidant therapy (i.e., rh-SOD).  Subsequently, my laboratory was the first to demonstrate that nitric oxide donors protected the ischemic myocardium.   Nitric oxide therapy for acute myocardial infarction has recently been translated to the clinic with a number of clinical trials investigating nitric oxide based therapies for the treatment of acute myocardial infarction and heart failure.

 

a.   Tsao, P.S., N. Aoki, D.J. Lefer, G. Johnson III and A.M. Lefer.  Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat. Circulation 82:1402-1412, 1990. PMID: 2401073.

 

b.   Lefer, D.J., K. Nakanishi, J. Vinten-Johansen, X-L. Ma, and A.M. Lefer.  Cardiac venous endothelial dysfunction following myocardial ischemia and reperfusion in dogs.  Am. J. Physiol.  263:H850-H856, 1992. PMID: 1415612.

 

c.   Lefer, D.J., K. Nakanishi, W.E. Johnston, and J. Vinten-Johansen.  Anti-neutrophil and myocardial protecting actions of a novel nitric oxide donor following acute myocardial ischemia and reperfusion in dogs.  Circulation 88:2337-2350, 1993. PMID: 8222127.

 

d.   Pabla, R., A.J. Buda, A.M. Shin, D.M. Flynn, M.J. Curtis, and D.J. Lefer.  Nitric oxide attenuates neutrophil-mediated myocardial contractile dysfunction following ischemia and reperfusion.  Circulation Research 78:65-72, 1996. PMID: 8603507.

 

My research work continued with investigations into the translation of nitric oxide therapeutics for cardiovascular diseases. One of the major limitations of nitric oxide therapeutics is the extremely short half-life of NO coupled with the fact that the vast majority of NO donors exhibit very poor pharmacokinetic profiles.  Research from other laboratories revealed that following generation from endothelial nitric oxide synthase (eNOS), nitric oxide was stored as nitrite in high concentrations in the circulation and in all tissues including the heart.  In 2005 my research team was the first to demonstrate that the highly stable nitric oxide intermediate, nitrite, protected the ischemic-reperfused myocardium in vivo. This seminal paper provided the foundation for the use of nitrite therapy for a myriad of cardiovascular disease states.  At present there are numerous clinical studies and clinical trials investigating both nitrate and nitrate therapy for various forms of cardiovascular and other disease states.

 

a.   Duranski, M.R., J.J.M. Greer, A. Dejam, J. Sathya, N. Hogg, W. Langston, C.G. Kevil, R.P. Patel, M.T. Gladwin, and D.J. Lefer.  Cytoprotective effects of nitrite during ischemia-reperfusion of the heart and liver.  J. Clin. Invest. 115:1232-1240, 2005. PMCID: PMC1077170.

 

b.   Bryan N.S., J.W. Calvert, J.W. Elrod, S. Gundewar, and D.J. Lefer. Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury.  Proc. Natl. Acad. Sci., U.S.A., 104:19144-19149, 2007. PMCID: PMC2141922.

 

c.   Elrod, J.W., J.W. Calvert, S. Gundewar, N.S. Bryan, and D.J. Lefer.  Nitric oxide promotes distant organ protection:  Evidence for an endocrine role of nitric oxide.  Proc. Natl. Acad. Sci., U.S.A.  105:11430-11435, 2008. PMCID: PMC2516252.

 

d.   Bhushan, S., K. Kondo, D. Polhemus, C. Nicholson, Y. Tao, H. Huang, V.V. Georgiopoulou, T. Murohara, J.W. Calvert, J. Butler, and D.J. Lefer.  Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide (NO) and nitrosothiol mediated cytoprotective signaling. Circulation Research 114:1281-1291, 2014.  PMID 24599803.

 

My research program has continued in the area of gaseous signaling molecules in cardiovascular physiology and pathology. We have investigated the role of hydrogen sulfide (H2S) in cardiovascular diseases including acute myocardial infarction, heart failure, and hypertension.  My laboratory was the first to demonstrate that H2S levels are significantly reduced in animal models of heart failure and also in humans suffering from heart failure. These results are significant and have provided a foundation for the further investigation of the protective effects of H2S-based therapy and potential clinical utility of H2S in acute MI and heart failure.  Finally, my research group was the first to demonstrate the direct cross-talk between H2S and NO signaling in a landmark study describing the effects of H2S on endothelial nitric oxide synthase (eNOS) activation status.  This study provides important mechanistic information regarding H2S-NO signaling that can potentially be utilized for the treatment of cardiovascular disease.  H2S-based therapies are currently in clinical trials for a number of disease states.

 

a.   Elrod, J.W., J.W. Calvert, J. Morrison, J.E. Doeller, D.W. Kraus, L. Tao, R. Scalia, L. Kiss, C. Szabo, H. Kimura, B. Malester, W.A. Coetzee, C. Chow, and D.J. Lefer.  Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury via preservation of mitochondrial function. Proc. Natl. Acad. Sci., U.S.A., 104:15560-15565, 2007. PMCID: PMC2000503.

 

b.   Calvert, J.W., M. Elston, C.K. Nicholson, S. Gundewar, S. Jha, J.W. Elrod, A. Ramachandran, and D.J. Lefer.  Genetic and pharmacologic hydrogen sulfide therapy attenuates ischemia-induced heart failure in mice.  Circulation 122:11-19, 2010. PMCID: PMC2955293.

 

c.   Kondo, K., S. Bhushan, A.L. King, S.D. Prabhu, T. Hamid, S. Koenig, T. Murohara, B.L. Predmore, G. Gojon Sr., G. Gojon, Jr., R. Wang, N. Karusula, C.K. Nicholson, J.W. Calvert, and D.J. Lefer.  Hydrogen sulfide protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase.  Circulation 127:1116-1127, 2013.  PMCID: PMC3670187.

 

d.   King, A.L., D.J. Polhemus, S. Bhushan, H. Otsuka, K. Kondo, C. Nicholson, J.M. Bradley, K.N. Islam, J.W. Calvert, Y. Tao, T.R. Dugas, E.E. Kelley. J.W. Elrod, P.L. Huang, R. Wang, and D.J. Lefer.  Hydrogen sulfide cardioprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc. Natl. Acad. Sci., USA.  111-3182-3187, 2014. PMCID: PMC3939925.