Published Online
on January 19, 2004

A more recent version of this article appeared on February 3, 2004

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Submitted on July 31, 2002
Revised on September 25, 2003
Accepted on October 27, 2003

Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway. Role of Asymmetric Dimethylarginine in Transplant Arteriosclerosis

Michael Weis MD, Thomas N. Kledal PhD, Ken Y. Lin , Shyam N. Panchal , S. Z. Gao MD, Hannah A. Valantine MD, Edward S. Mocarski PhD, and John P. Cooke MD, PhD^*

From the Division of Cardiovascular Medicine (M.W., K.Y.L., S.N.P., S.Z.G., H.A.V., J.P.C.) and the Department of Microbiology and Immunology (T.N.K., E.S.M.), Stanford University School of Medicine, Stanford, Calif; and Medizinische Klinik I (M.W.), University Hospital Munich-Grosshadern, Ludwig Maximilians-University of Munich, Munich, Germany.

^* To whom correspondence should be addressed. E-mail: john.cooke{at}stanford.edu.

Background--We hypothesized that cytomegalovirus (CMV) may contribute to the vasculopathy observed in cardiac allograft recipients by impairing the endothelial nitric oxide synthase pathway. We focused on asymmetric dimethylarginine (ADMA, the endogenous inhibitor of nitric oxide synthase) as a potential mediator of the adverse vascular effect of CMV.

Methods and Results--Heart transplant recipients manifested elevated plasma ADMA levels compared with healthy control subjects. Transplant patients with CMV DNA-positive leukocytes had higher plasma ADMA concentrations and more extensive transplant arteriopathy (TA). Human microvascular endothelial cells infected with the CMV isolates elaborated more ADMA. The increase in ADMA was temporally associated with a reduction in the activity of dimethylarginine dimethylaminohydrolase (DDAH, the enzyme that metabolizes ADMA). Infected cultures showed high levels of oxidative stress with enhanced endothelial production of superoxide anion.

Conclusions--CMV infection in human heart transplant recipients is associated with higher ADMA elevation and more severe TA. CMV infection in endothelial cells increases oxidative stress, impairs DDAH activity, and increases ADMA elaboration. CMV infection may contribute to endothelial dysfunction and TA by dysregulation of the endothelial nitric oxide synthase pathway.

Key words: endothelium • transplantation • viruses • arteriosclerosis

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