NO counterbalances HO-1 overexpression-induced acceleration of hepatocyte proliferation in mice

• Published in: Laboratory investigation Vol. 87; no. 6; pp. 602 - 612
• Main Authors: Schuett, Harald, Eipel, Christian, Maletzki, Claudia, Menger, Michael D, Vollmar, Brigitte
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.06.2007; Nature Publishing Group US; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Biotechnology; carbon monoxide; Cell Proliferation; Fundamental and applied biological sciences. Psychology; Heme Oxygenase-1 - analysis; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hepatectomy; Hepatocytes - enzymology; Hepatocytes - physiology; Immunohistochemistry; intravital fluorescence microscopy; Investigative techniques, diagnostic techniques (general aspects); Kinetics; Laboratory Medicine; Liver Regeneration; Male; Medical sciences; Medicine; Medicine & Public Health; Methadyl Acetate - pharmacology; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Molsidomine - pharmacology; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type II - analysis; Pathology; Proliferating Cell Nuclear Antigen - analysis; proliferation; Protoporphyrins - pharmacology; research-article; shear stress; carbon monoxide; hepatectomy; intravital fluorescence microscopy; shear stress; proliferation; Cell proliferation; Biotechnology; Digestive system; Enzyme; Liver; Rodentia; Heme oxygenase (decyclizing); Gene overexpression; Hepatectomy; Vertebrata; Mammalia; Hepatocyte; Mouse; Animal; Clinical biology; Shear stress; Oxidoreductases; Carbon monoxide; Acceleration; Fluorescence microscopy
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.3700548

The trigger for liver regeneration, including shear stress, has been the subject of ongoing debate. Blood vessel-derived gaseous molecules carbon monoxide (CO) and nitric oxide (NO) regulate vascular tone and play an important role in liver regeneration. In heme oxygenase-1 (HO-1) transgenic mice, it has been shown that CO-mediated impairment of vasorelaxation is an NO-dependent event. We therefore studied liver regeneration in HO-1 overexpressing animals in dependency of NO availability. Mice were subjected to 2/3 hepatectomy and were treated with either cobalt protoporphyrin-IX for induction of CO-liberating HO-1, Nω-nitro-L-arginine methyl ester (L-NAME) for blockade of NO synthase (NOS) or both. Application of molsidomine in L-NAME treated animals served for resubstitution of NO. Vehicle-treated animals served as respective control animals. We examined 5-bromo-2′-deoxyuridine incorporation and proliferating cell nuclear antigen expression as well as HO-1 and NOS-2 protein levels. Intrahepatic red blood cell velocity and volumetric blood flow were evaluated by in vivo fluorescence microscopy as indicators for microvascular shear stress. Hepatic regeneration remained unaffected by L-NAME application for NOS blockade. However, NOS blockade in HO-1 induced animals caused increased 5-bromo-2′-deoxyuridine and proliferating cell nuclear antigen measures of liver regeneration. In parallel, these animals revealed increased velocities and volumetric blood flow in the terminal afferent vessels and postsinusoidal venules. These local hemodynamic changes including enhanced hepatocyte proliferation could be reversed by NO liberation via molsidomine. The present findings stress the role of NO to counterbalance vascular tone in HO-1 overexpressing animals for maintenance of adequate perfusion and salutary shear force within the hepatic microvasculature upon liver resection.