Published online before print June 8, 2006, doi: 10.1161/01.RES.0000231306.03510.77
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Submitted on September 13, 2005
Revised on May 22, 2006
Accepted on May 30, 2006
eNOS Gene Therapy Exacerbates Hepatic Ischemia-Reperfusion Injury in Diabetes. A Role for eNOS Uncoupling
John W. Elrod ;
From the Department of Medicine (J.W.E., M.R.D., D.J.L.), Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY; Department of Molecular and Cellular Physiology (W.L., J.J.M.G.); Department of Pharmacology, Toxicology and Neuroscience (T.R.D.); and Department of Pathology (C.G.K.), Louisiana State University Health Sciences Center, Shreveport; Department of Emergency Medicine (L.T.), Thomas Jefferson University, Philadelphia, Pa; and Department of Cardiology (H.C.C.), Johns Hopkins Hospital, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: dlefer{at}aecom.yu.edu.
Previous studies indicate that endothelial nitric oxide synthase (eNOS) function is impaired in diabetes as a result of increased vascular generation of reactive oxygen species. We hypothesized that eNOS gene therapy would augment NO· bioavailability and protect against hepatic ischemia-reperfusion (I-R) injury in type 2 diabetes mellitus. We developed a transgenic (Tg) diabetic mouse in which eNOS is systemically overexpressed. We also examined the effects of hepatic eNOS adenovirus therapy in diabetic mice. Diabetic (db/db) and nondiabetic mice were subjected to hepatic I-R injury. In nondiabetic mice, genetic overexpression of eNOS (both eNOS-Tg and eNOS adenovirus) resulted in hepatoprotection. In contrast, hepatic I-R injury was significantly increased in the db/db eNOS-Tg mouse, as serum alanine aminotransaminase (ALT) levels were increased by 332% when compared with diabetic controls. Similarly, eNOS adenovirus treatment resulted in a 317% increase in serum ALT levels as compared with diabetic controls. We determined that hepatic eNOS was dysfunctional in the db/db mouse and increased genetic expression of eNOS resulted in greater production of peroxynitrite. Treatment with the eNOS cofactor tetrahydrobiopterin (BH4) or the BH4 precursor sepiapterin resulted in a significant decrease in serum ALT levels following I-R injury. We present clear examples of the protective and injurious nature of NO· therapy in I-R. Our data indicate that eNOS exists in an "uncoupled" state in the setting of diabetes and that "recoupling" of the eNOS enzyme with cofactor therapy is beneficial.
Key words: diabetes mellitus • tetrahydrobiopterin • eNOS phosphorylation • sepiapterin • peroxynitrite
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