Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis.
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.


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.
Weis
Michael
M
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif 94305-5406, USA.
Kledal
Thomas N
TN
Lin
Ken Y
KY
Panchal
Shyam N
SN
Gao
S Z
SZ
Valantine
Hannah A
HA
Mocarski
Edward S
ES
Cooke
John P
JP
D000581:Amidohydrolases / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood* / Q000378:metabolism / Q000502:physiology; D002318:Cardiovascular Diseases / Q000453:epidemiology; D002478:Cells, Cultured; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood / Q000209:etiology / Q000821:virology*; D006152:Cyclic GMP / Q000096:biosynthesis; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000201:enzymology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000821:virology; D005260:Female; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress; D012307:Risk Factors; D015398:Signal Transduction
D009573:Nitrites; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase; D006152:Cyclic GMP