Journal
JOURNAL OF HEPATOLOGY
Volume 62, Issue 2, Pages 325-331Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2014.08.024
Keywords
Portal hypertension; ADMA; DDAH-1; Nitric oxide
Categories
Funding
- UCL-Business Proof of Concept award
- National Institutes of Health [DK082600]
- Medical Research Council [G0601448] Funding Source: researchfish
- MRC [G0601448] Funding Source: UKRI
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Background & Aims: Portal hypertension is characterized by reduced hepatic eNOS activity. Asymmetric-dimethylarginine (ADMA), an eNOS inhibitor, is elevated in cirrhosis and correlates with the severity of portal hypertension. Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the key enzyme metabolizing hepatic ADMA. This study characterized DDAH-1 in cirrhosis, and explored hepatic DDAH-1 reconstitution through farnesoid X receptor (FXR) agonism and DDAH-1 gene therapy. Methods: DDAH-1 immunohistochemistry was conducted on human cirrhosis and healthy liver tissue. Subsequently, sham-operated or bile-duct-ligated (BDL) cirrhosis rats were treated with the FXR agonist obeticholic acid (OA, 5 mg/kg) or vehicle for 5 days. Further, animals underwent hydrodynamic injection with DDAH-1-expressing plasmid or saline control, which resulted in the following groups: sham + saline, BDL + saline, BDL + DDAH-1-plasmid. Portal pressure (PP) measurements were performed. Plasma ALT was measured by COBAS INTEGRA, DDAH-1 expression by qPCR and Western blot, eNOS activity by radiometric assay. Results: Immunohistochemistry and Western-blotting confirmed hepatic DDAH-1 was restricted to hepatocytes, and expression decreased significantly in cirrhosis. In BDL rats, reduced DDAH-1 expression was associated with elevated hepatic ADMA, reduced eNOS activity and high PP. OA treatment significantly increased DDAH-1 expression, reduced hepatic tissue ADMA, and increased liver NO generation. PP was significantly reduced in BDL + OA vs. BDL + vehicle (8 +/- 1 vs. 13.5 +/- 0.6 mmHg; p < 0.01) with no change in the mean arterial pressure (MAP). Similarly, DDAH-1 hydrodynamic injection significantly increased hepatic DDAH-1 gene and protein expression, and significantly reduced PP in BDL + DDAH-1 vs. BDL + saline (p < 0.01). Conclusions: This study demonstrates DDAH-1 is a specific molecular target for portal pressure reduction, through actions on ADMA-mediated regulation of eNOS activity. Our data support translational studies, targeting DDAH-1 in cirrhosis and portal hypertension. (C) 2014 Published by Elsevier B. V. on behalf of the European Association for the Study of the Liver.
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