Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats
✍ Scribed by Yung-Chang Chen; Pere Ginès; Jianhui Yang; Sandra N. Summer; Sandor Falk; Nash S. Russell; Robert W. Schrier
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 401 KB
- Volume
- 39
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Vascular heme oxygenase (HO) regulates vascular tone in normal conditions and in some pathologic circumstances (e.g., sepsis). However, its possible role in the pathogenesis of arterial vasodilation in cirrhosis is unknown. To address this question, the expression and activity of HO in arterial vessels was studied in rats at 1, 2, and 4 weeks after bile duct ligation (BDL) or sham operation. A progressively increased expression of HO-1 was found in aorta and mesenteric arteries of BDL rats in a close chronologic relationship with the progression from acute cholestatic liver injury (1 week) to the fully developed cirrhosis with intense systemic arterial vasodilation (4 weeks). No changes were found in the expression of the constitutive isoform HO-2. HO-1 was mainly located in vascular smooth muscle cells of the arterial wall. Aortic HO activity increased in parallel with the expression of HO-1 (up to 600% in rats with cirrhosis compared with sham rats) and correlated with hemodynamic parameters. Increased expression of HO-1 and HO activity were also found in other organs, such as liver and spleen, though to a lesser extent compared with vascular tissue. The acute administration of an inhibitor of HO to cirrhotic rats, at a dose that normalized aortic HO activity, was associated with significantly greater effects on arterial pressure, total peripheral vascular resistance, and cardiac index, compared with effects in sham rats. In conclusion, these findings are consistent with a role for HO in the pathogenesis of arterial vasodilation in cirrhosis. (HEPATOLOGY 2004;39:1075-1087.)
A characteristic feature of liver cirrhosis is the existence of important disturbances in the systemic circulation that manifest as marked arterial vasodilation, which occurs mainly in the splanchnic circula-tion and results in a reduction of total peripheral vascular resistance and arterial pressure and a secondary increase in cardiac output. These abnormalities are of key importance to the development of several major complications of cirrhosis, including hepatorenal syndrome, ascites, spontaneous bacterial peritonitis, dilutional hyponatremia, and hepatopulmonary syndrome. 1,2 Therefore, it is not surprising that the possible mediators of this arterial vasodilation have been the focus of a major research effort in recent years. Among others, it appears that an increased vascular production of nitric oxide (NO) could play an important role. [3][4][5][6][7][8] Recent studies suggest a possible role for carbon monoxide (CO), an end product of the heme oxygenase (HO) pathway, in the pathogenesis of arterial vasodilation in cirrhosis. 9 -11 HO is an enzyme that catabolizes heme derived from heme-containing proteins-especially hemoglobin-to biliverdin, which is then rapidly transformed to bilirubin and CO. 12,13 CO has a number of important biologic effects-including vasodilation through activation of the enzyme guanylate cyclase of vascular smooth muscle cells-and seems to play an important role in the