Increased production of ADAMTS13 in hepatic stellate cells contributes to enhanced plasma ADAMTS13 activity in rat models of cholestasis and steatohepatitis

Summary

Although hepatic stellate cells, endothelial cells, glomerular podocytes and plateles were reported to be a source of ADAMTS13, it is not clarified which source is involved in the regulation of plasma ADAMTS13 activity. It was demonstrated previously that selective hepatic stellate cell damage in rats caused decreased plasma ADAMTS13 activity.To further elucidate the potential contribution of hepatic stellate cells to the regulation of plasma ADAMTS13 activity, this study examined plasma ADAMTS13 activity when hepatic stellate cells proliferate during the process of liver fibrosis by employing rat models of liver fibrosis due to cholestasis, bile duct ligation, and steatohepatitis, a choline-deficient L-amino acid-defined-diet. ADAMTS13 expression was increased with co-localisation with smooth muscle α-actin, a marker of hepatic stellate cells, in bile duct-ligated livers up to four weeks, in which a close correlation between ADAMTS13 and smooth muscle α-actin mRNA expressions was determined. Plasma ADAMTS13 activity, measured by a sandwich ELISA involving a specific substrate to ADAMTS13, was increased in bile duct-ligated rats with a significant correlation with ADAMTS13 mRNA expression levels in the liver. Furthermore, ADAMTS13 mRNA expression was increased with enhanced mRNA expression in smooth muscle α-actin in the livers of rats fed a choline-deficient L-amino aciddefined-diet for 16 weeks, in which increased plasma ADAMTS13 activity was determined. Thus, increased plasma ADAMTS13 activity in cholestasis and steatohepatitis in rats may be due, at least in part, to enhanced ADAMTS13 production in the liver, suggesting a significant role of hepatic stellate cells in the regulation of plasma ADAMTS13 activity.

Keywords

ADAMTS13 - hepatic stellate cell - smooth muscle α-actin - bile duct ligation - steatohepatitis

• References

• 1 Furlan M, Robles R, Solenthaler M. et al. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997; 89: 3097-3103.
• 2 Banno F, Kokame K, Okuda T. et al. Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. Blood 2006; 107: 3161-3166.
• 3 Chauhan AK, Walsh MT, Zhu G. et al. The combined roles of ADAMTS13 and VWF in murine models of TTP, endotoxemia, and thrombosis. Blood 2008; 111: 3452-3457.
• 4 Kinoshita S, Yoshioka A, Park YD. et al. UpshawSchulman syndrome revisited: a concept of congenital thrombotic thrombocytopenic purpura. Int J Hematol 2001; 74: 101-108.
• 5 Sasahara Y, Kumaki S, Ohashi Y. et al. Deficient activity of von Willebrand factor-cleaving protease in patients with Upshaw-Schulman syndrome. Int J Hematol 2001; 74: 109-114.
• 6 Hommais A, Rayes J, Houllier A. et al. Molecular characterization of four ADAMTS13 mutations responsible for congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). Thromb Haemost 2007; 98: 593-599.
• 7 Furlan M, Robles R, Solenthaler M. et al. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood 1998; 91: 2839-2846.
• 8 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585-1594.
• 9 Yagita M, Uemura M, Nakamura T. et al. Development of ADAMTS13 inhibitor in a patient with hepatitis C virus-related liver cirrhosis causes thrombotic thrombocytopenic purpura. J Hepatol 2005; 42: 420-421.
• 10 Tsai HM, Raoufi M, Zhou W. et al. ADAMTS13-binding IgG are present in patients with thrombotic thrombocytopenic purpura. Thromb Haemost 2006; 95: 886-892.
• 11 Luken BM, Turenhout EA, Kaijen PH. et al. Amino acid regions 572-579 and 657-666 of the spacer domain of ADAMTS13 provide a common antigenic core required for binding of antibodies in patients with acquired TTP. Thromb Haemost 2006; 96: 295-301.
• 12 Ono T, Mimuro J, Madoiwa S. et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 2006; 107: 528-534.
• 13 Zheng X, Chung D, Takayama TK. et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001; 276: 41059-41063.
• 14 Soejima K, Mimura N, Hirashima M. et al. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease?. J Biochem (Tokyo) 2001; 130: 475-480.
• 15 Cal S, Obaya AJ, Llamazares M. et al. Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. Gene 2002; 283: 49-62.
• 16 Uemura M, Tatsumi K, Matsumoto M. et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood 2005; 106: 922-924.
• 17 Niiya M, Uemura M, Zheng XW. et al. Increased ADAMTS-13 proteolytic activity in rat hepatic stellate cells upon activation in vitro and in vivo. J Thromb Haemost 2006; 04: 1063-1070.
• 18 Zhou W, Inada M, Lee TP. et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest 2005; 85: 780-788.
• 19 Turner N, Nolasco L, Tao Z. et al. Human endothelial cells synthesize and release ADAMTS-13. J Thromb Haemost 2006; 04: 1396-1404.
• 20 Manea M, Kristoffersson A, Schneppenheim R. et al. Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura. Br J Haematol 2007; 138: 651-662.
• 21 Liu L, Choi H, Bernardo A. et al. Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. J Thromb Haemost 2005; 03: 2536-2544.
• 22 Kume Y, Ikeda H, Inoue M. et al. Hepatic stellate cell damage may lead to decreased plasma ADAMTS13 activity in rats. FEBS Lett 2007; 581: 1631-1634.
• 23 Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134: 1655-1669.
• 24 Ikeda H, Wu GY, Wu CH. Lipocytes from fibrotic rat liver have an impaired feedback response to procollagen propeptides. Am J Physiol 1993; 264: G157-162.
• 25 Jin H, Yamamoto N, Uchida K. et al. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet. Biochem Biophys Res Commun 2007; 364: 801-807.
• 26 Mannucci PM, Canciani MT, Forza I. et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98: 2730-2735.
• 27 Uemura M, Fujimura Y, Matsumoto M. et al. Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost 2008; 99: 1019-1029.
• 28 Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C The METAVIR Cooperative Study Group. Hepatology 1996; 24: 289-293.
• 29 Kato S, Matsumoto M, Matsuyama T. et al. Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity. Transfusion 2006; 46: 1444-1452.
• 30 Kountouras J, Billing BH, Scheuer PJ. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol 1984; 65: 305-311.
• 31 Feys HB, Canciani MT, Peyvandi F. et al. ADAMTS13 activity to antigen ratio in physiological and pathological conditions associated with an increased risk of thrombosis. Br J Haematol 2007; 138: 534-540.
• 32 Kokame K, Nobe Y, Kokubo Y. et al. FRETSVWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol 2005; 129: 93-100.
• 33 Meyer SC, Sulzer I, Lammle B. et al. Hyperbilirubinemia interferes with ADAMTS-13 activity measurement by FRETS-VWF73 assay: diagnostic relevance in patients suffering from acute thrombotic microangiopathies. J Thromb Haemost 2007; 05: 866-867.
• 34 Kavakli K, Canciani MT, Mannucci PM. Plasma levels of the von Willebrand factor-cleaving protease in physiological and pathological conditions in children. Pediatr Hematol Oncol 2002; 19: 467-473.
• 35 Uemura M, Matsuyama T, Ishikawa M. et al. Decreased activity of plasma ADAMTS13 may contribute to the development of liver disturbance and multiorgan failure in patients with alcoholic hepatitis. Alcohol Clin Exp Res 2005; 29 (Suppl. 12) 264S-271S.
• 36 Lisman T, Bongers TN, Adelmeijer J. et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44: 53-61.