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Nitric oxide synthase 1 is partly compensating for nitric oxide synthase 3 deficiency in nitric oxide synthase 3 knock-out mice and is elevated in murine and human cirrhosis

Authors


Prof. Jürg Reichen, MD, Department of Clinical Pharmacology, University of Berne Murtenstrasse 35, 3010 Berne, Switzerland.
Tel: +41 31 632 8711
e-mail: reichen@ikp.unibe.ch

Abstract

Abstract:
Background:
The role of endothelial nitric oxide synthase 3 (NOS-3) in the hyperdynamic circulation associated with cirrhosis is established but not that of the neuronal (NOS-1) isoform. We therefore investigated aortic NOS-1 levels in NOS-3 knock-out (KO) and wildtype (WT) mice and in hepatic arteries of patients.

Methods: Mice rendered cirrhotic by bile duct ligation (BDL) were compared with sham-operated controls. Hepatic arteries of cirrhotic patients were collected during liver transplantation; donor vessels served as controls. mRNA levels were quantified by real-time PCR, protein levels by Western blotting and NO production by Nω-nitro-l-arginine methyl ester inhibitable arginine–citrulline assay.

Results: Aortae of NOS-3 KO mice exhibited higher NOS-1mRNA (5.6-fold, P<0.004) and protein levels (8.8-fold) compared with WT. NO production in aortae of NOS-3 KO mice was 52% compared with WT (P=0.002). BDL increased NOS-1 mRNA (2.4-fold, P=0.01) and protein (7.1-fold) levels in aortae of WT, but no further in the NOS-3 KO mice. Hepatic artery NOS-1 mRNA levels in cirrhotic patients were markedly increased compared with controls (24.5-fold, P=0.0007).

Conclusions: Increased NOS-1 mRNA and protein levels and partially maintained in vitro NO-production in aortae of NOS-3 KO mice suggest that NOS-1 may partially compensate for NOS-3 deficiency. BDL-induced increase in aortic NOS-1 mRNA and protein levels hint that not only NOS-3, but also NOS-1 may be involved in the regulation of systemic hyperdynamic circulation and portal hypertension. Upregulation of NOS-1 mRNA levels in hepatic arteries of portal hypertensive patients suggests possible clinical significance for these experimental findings.

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