Nitric oxide synthase and heme oxygenase expressions in human liver cirrhosis.
OBJECTIVE
Portal hypertension is a common complication of liver cirrhosis. Intrahepatic pressure can be elevated in several ways. Abnormal architecture affecting the vasculature, an increase in vasoconstrictors and increased circulation from the splanchnic viscera into the portal system may all contribute. It follows that endogenous vasodilators may be able to alleviate the hypertension. We therefore aimed to investigate the levels of endogenous vasodilators, nitric oxide (NO) and carbon monoxide (CO) through the expression of nitric oxide synthase (NOS) and heme oxygenase (HO).


METHODS
Cirrhotic (n=20) and non-cirrhotic (n=20) livers were obtained from patients who had undergone surgery. The mRNA and protein expressions of the various isoforms of NOS and HO were examined using competitive PCR, Western Blot and immunohistochemistry.


RESULTS
There was no significant change in either inducible NOS (iNOS) or neuronal NOS (nNOS) expressions while endothelial NOS (eNOS) was up-regulated in cirrhotic livers. Concomitantly, caveolin-1, an established down-regulator of eNOS, was up-regulated. Inducible HO-1 and constitutive HO-2 were found to show increased expression in cirrhotic livers albeit in different localizations.


CONCLUSIONS
The differences of NOS expression might be due to their differing roles in maintaining liver homeostasis and/or involvement in the pathology of cirrhosis. Sheer stress within the hypertensive liver may induce increased expression of eNOS. In turn, caveolin-1 is also increased. Whether this serves as a defense mechanism against further cirrhosis or is a consequence of cirrhosis, is yet unknown. The elevated expression of HO-1 and HO-2 suggest that CO may compensate in its role as a vasodilator albeit weakly. It is possible that CO and NO have parallel or coordinated functions within the liver and may work antagonistically in the pathophysiology of portal hypertension.
Department of Biochemistry, Faculty of Medicine, National University of Singapore, Block MD4A, #01-03 5 Science Drive 2, 117597, Singapore.
Beatrice J
BJ
Goh
Bee Tee
BT
Tan
Wei Min
WM
Hon
Kang Hoe
KH
Lee
Hoon Eng
HE
Khoo
D000328:Adult; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D006419:Heme Oxygenase (Decyclizing)