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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
Author(s) -
Biecker Erwin,
Neef Markus,
Sägesser Hans,
Shaw Sidney,
Koshy Abraham,
Reichen Jürg
Publication year - 2004
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2004.0933.x
Subject(s) - nitric oxide synthase , medicine , endocrinology , nitric oxide , cirrhosis , endothelial nos , citrulline , chemistry , nitric oxide synthase type iii , messenger rna , hyperdynamic circulation , arginine , portal hypertension , enos , biochemistry , amino acid , gene
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 N ω ‐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.