Salvianolic acid B attenuates hepatocyte apoptosis by regulating mediators in death receptor and mitochondrial pathways

Salvianolic acid B (Sal B) is a water-soluble compound found in the traditional Chinese medicine, Radix Salviae miltiorrhizae, and has been widely used to treat a variety of diseases in Asian cultures. Sal B was shown to inhibit apoptosis in many cell types, but its effect on hepatocyte apoptosis is unknown. In this study, we attempt to show that Sal B attenuates hepatocyte apoptosis and hepatic injury induced by lipopolysaccharide and D-galactosamine in mice. Sal B also inhibits apoptosis that is induced by the death receptor in the HL-7702 hepatocyte cell line. Apoptosis in vitro is determined by flow cytometry, DNA electrophoresis and high content screening assay. The antiapoptotic effect is generated by reducing the expression of tumor necrosis factor α receptor type 1, balancing the expression of Bcl-2 family members, decreasing the release of cytochrome C from the mitochondria into the cytosol and inhibiting activated Caspase-3. These findings suggest that Sal B can effectively inhibit hepatocyte apoptosis as well as the underlying mechanisms related to regulating mediators in death receptor and mitochondrial pathways.

[1]  M. Duan,et al.  Salvianolic acid B, an antioxidant from Salvia miltiorrhiza, prevents 6-hydroxydopamine induced apoptosis in SH-SY5Y cells. , 2008, The international journal of biochemistry & cell biology.

[2]  Yi-Yang Hu,et al.  [Effects of salvianolic acid B on expressions of TGF-beta1 and its receptors in liver of rats with dimethylnitrosamine-induced hepatic fibrosis]. , 2005, Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine.

[3]  J. Tschopp,et al.  Induction of TNF Receptor I-Mediated Apoptosis via Two Sequential Signaling Complexes , 2003, Cell.

[4]  C. Liu,et al.  Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B. , 2002, World journal of gastroenterology.

[5]  P. Tu,et al.  Effects of salvianolic acids on erythrocyte deformability in oleic acid induced acute lung injury in rabbits. , 2006, Clinical hemorheology and microcirculation.

[6]  W. Bursch,et al.  Apoptosis is induced by transforming growth factor‐β1 within 5 hours in regressing liver without significant fragmentation of the DNA , 1993, Hepatology.

[7]  Pingliu,et al.  Clinical observation of salvianolic acid Bin treatment of liver fibrosis in chronic hepatitisB , 2002 .

[8]  M. Leist,et al.  Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. , 1995, The American journal of pathology.

[9]  G. Du,et al.  Salvianolic acid B protects brain against injuries caused by ischemia-reperfusion in rats. , 2000, Acta pharmacologica Sinica.

[10]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[11]  G. Majno,et al.  Apoptosis, oncosis, and necrosis. An overview of cell death. , 1995, The American journal of pathology.

[12]  G. Gores,et al.  Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. , 2001, Journal of hepatology.

[13]  Suzanne Cory,et al.  The Bcl-2 family: roles in cell survival and oncogenesis , 2003, Oncogene.

[14]  P. Krammer,et al.  Suramin inhibits death receptor–induced apoptosis in vitro and fulminant apoptotic liver damage in mice , 2004, Nature Medicine.

[15]  G. Gores,et al.  Apoptosis: a mechanism of acute and chronic liver injury , 2005, Gut.

[16]  Junwei Yang,et al.  Preventive effects of salvianolic acid B on transforming growth factor-beta1-induced epithelial-to-mesenchymal transition of human kidney cells. , 2009, Biological & pharmaceutical bulletin.

[17]  Takahiro Suzuki,et al.  Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses. , 2004, Gastroenterology.

[18]  Ping Liu,et al.  Effects of salvianolic acid-B on TGF-beta 1 stimulated hepatic stellate cell activation and its intracellular signaling. , 2002, Zhonghua yi xue za zhi.

[19]  Jian-Dong Huang,et al.  Salvianolic Acid B Inhibits Hydrogen Peroxide-Induced Endothelial Cell Apoptosis through Regulating PI3K/Akt Signaling , 2007, PloS one.

[20]  N. Thornberry,et al.  Caspases: killer proteases. , 1997, Trends in biochemical sciences.

[21]  J. Dhainaut,et al.  LPS challenge in D-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock. , 1999, American journal of respiratory and critical care medicine.

[22]  F. Liao,et al.  Protective effect of tetramethylpyrazine and salvianolic acid B on apoptosis of rat cerebral microvascular endothelial cell under high shear stress. , 2008, Clinical hemorheology and microcirculation.

[23]  G. Gores,et al.  Apoptosis and necrosis in the liver: A tale of two deaths? , 2006, Hepatology.

[24]  G. Gores,et al.  Apoptosis and liver disease. , 2000, The American journal of medicine.

[25]  P. Vandenabeele,et al.  Cell death induction by receptors of the TNF family: towards a molecular understanding , 1997, FEBS letters.

[26]  G. Gores,et al.  The Caspase Inhibitor IDN-6556 Attenuates Hepatic Injury and Fibrosis in the Bile Duct Ligated Mouse , 2004, Journal of Pharmacology and Experimental Therapeutics.