Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver
Version of Record online: 15 SEP 2008
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd
Volume 29, Issue 5, pages 650–660, May 2009
How to Cite
Van Landeghem, L., Laleman, W., Vander Elst, I., Zeegers, M., Van Pelt, J., Cassiman, D. and Nevens, F. (2009), Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver. Liver International, 29: 650–660. doi: 10.1111/j.1478-3231.2008.01857.x
- Issue online: 7 APR 2009
- Version of Record online: 15 SEP 2008
- Received 8 May 2008Accepted 7 July 2008
- hepatic microcirculation;
- intrahepatic vascular resistance;
- portal hypertension;
- stellate cell
Background/Objective: Carbon monoxide (CO) produced by haem-oxygenase isoforms (HO-1 & HO-2) is involved in the regulation of systemic vascular tone. We aimed to elucidate the vasoregulatory role of CO in the microcirculation in normal and thioacetamide cirrhotic rat livers.
Methods: Haem-oxygenase expression was examined by Western blot. Total HO enzymatic activity was measured spectrophotometrically. Sensitivity of hepatic stellate cells (HSCs) to CO-mediated relaxation was studied by a stress-relaxed-collagen-lattice model. To define the relative role of CO, the CO-releasing molecule CORM-2, the HO-inhibitor zinc protoporphyrin-IX and the HO-1 inducer hemin were added to an in situ liver perfusion set-up. The topography of vasoactive CO production was evaluated by applying different CO- and nitric oxide-trapping reagents in the liver perfusion set-up and by immunohistochemistry.
Results: Western blot showed decreased expression of both HO isoenzymes (P<0.036 for HO-1; P<0.001 for HO-2) in cirrhotic vs normal rat livers, confirmed by the HO-activity assay (P=0.004). HSCs relaxed on exposure to CORM-2 (P=0.013). The increased intrahepatic vascular resistance (IHVR) of cirrhotic rats was attenuated by perfusion with CORM-2 (P=0.016) and pretreatment with hemin (P<0.001). Inhibition of HO caused a dose-related increase in IHVR in normal and cirrhotic liver. In normal liver, the haemodynamically relevant CO production occurred extrasinusoidally, while intrasinusoidally HO-1 predominantly regulated the microcirculation in cirrhotic livers.
Conclusion: We demonstrate a role for CO and HO in the regulation of normal and cirrhotic microcirculation. These findings are of importance in the pathophysiology of portal hypertension and establish CO/HO as novel treatment targets.