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Journal of Chinese Integrative Medicine ›› 2011, Vol. 9 ›› Issue (8): 878-887.doi: 10.3736/jcim20110810

• Original Experimental Research • Previous Articles     Next Articles

Chinese herbal medicine Xiayuxue Decoction inhibits liver angiogenesis in rats with carbon tetrachloride-induced liver fibrosis

Jin-xing Du1,2, Ping Liu1,2,3(), Ming-yu Sun1,2,3, Qing Tao1,2, Li-jun Zhang1,2, Gao-feng Chen1,2, Yi-yang Hu1,2,3, Cheng-hai Liu1,2,3, Lie-ming Xu1,2,3   

  1. 1. Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
    2. Shanghai Key Laboratory of Traditional Chinese Clinical Medicine,the Key Research Unit of Liver Diseases,State Administration of Traditionl Chinese Medicine of the Peopled Republic of China for Liver Diseases, Shanghai 201203, China
    3. E-institute of Traditional Chinese Internal Medicine of Shanghai Municipal Education Commission, Shanghai 201203, China
  • Received:2011-04-05 Accepted:2011-04-25 Online:2011-08-20 Published:2011-08-15

Objective: To evaluate the effects of Xiayuxue Decoction, a compound traditional Chinese medicine, on liver angiogenesis in rats with carbon tetrachloride (CCl4)-induced liver fibrosis.
Methods: Liver cirrhosis was induced by intraperitoneal injection of 50% CCl4-olive oil solution at the dose of 1 mL/kg body weight, twice per week for 9 consecutive weeks. After 3- and 6-week injection, 6 rats in the normal group and 6 rats in the model group were randomly sacrificed for dynamic observation. The survival rats of model group were randomly divided into model group (n=15) and Xiayuxue Decoction group (n=11). Six normal rats were used as a normal control. Xiayuxue Decoction was administered orally starting from the 7th week for 3 weeks. At the end of the ninth week, animals were sacrificed and liver tissues were harvested to measure histological changes, activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 and protein expressions of platelet endothelial cell adhesion molecule-1 (CD31), von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR2), complement decay-accelerating factor (DAF) and α-smooth muscle actin (α-SMA) in the liver tissues.
Results: Compared with the normal group, liver injury, fatty degeneration and collagen deposition were evidently observed in the model group and protein expressions of CD31, vWF, VEGF, VEGFR2, DAF and α-SMA were gradually increased. In addition, the activities of MMP-2 and MMP-9 in liver tissues were enhanced in the model group (P<0.01). Compared with 9-week model group, liver injury, fatty degeneration and collagen deposition were markedly inhibited by Xiayuxue Decoction; protein expressions of CD31, vWF, VEGF, VEGFR2, α-SMA and DAF and activities of MMP-2 and MMP-9 in the liver tissues were decreased in the Xiayuxue Decoction group (P<0.01).
Conclusion: The angiogenesis is evident and aggravating gradually during the progression of liver cirrhosis induced by CCl4. Xiayuxue Decoction inhibits the angiogenesis by decreasing the activities of MMP-2 and MMP-9, inhibiting the activation of hepatic stellate cells, and damaging the new vessel integrality.

Key words: carbon tetrachloride, liver cirrhosis, angiogenesis, drugs,Chinese herbal, rats

Figure 1

Pathological changes of liver tissues A: Photographs of hematoxylin-eosin staining (Light microscopy, ×200); B: Photographs of sirius red staining (Light microscopy, ×100). N: Normal group; 3W: 3-week model group; 6W: 6-week model group; 9W: 9-week model group; X: Xiayuxue Decoction group."

Figure 2

Protein expression of CD31 in liver tissues A: Photographs of immunofluorescence results (Fluorescence microscopy, ×200); B: Film negatives of Western blot results; C: Grayscale analysis (CD31-to-GAPDH ratio). N: Normal group; 3W: 3-week model group; 6W: 6-week model group; 9W: 9-week model group; X: Xiayuxue Decoction group. The values are represented as x±s. Expressions of CD31 protein in different (N, 9W and X) groups were 0.06±0.01, 0.74±0.03 and 0.08±0.01, respectively. H=6.25, P<0.05. **P<0.01, vs normal group; △△P<0.01, vs 9-week model group. CD31: platelet endothelial cell adhesion molecule-1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase."

Table 1

Scanning density integrals of expressions of CD31, vWF, VEGF, VEGFR2, α-SMA and DAF proteins in liver tissues of rats ($\bar{x}$±s)"

N 2 0.90±0.14 2.25±0.21 7.30±0.14 1.40±0 0±0 0±0
9W 3 11.33±0.21** 7.67±0.12** 15.10±0.26** 13.67±0.21** 7.10±0.20** 14.00±0.12**
X 3 1.33±0.06△△ 3.12±0.35△△ 12.37±0.25 11.20±0.36 1.97±0.15△△ 1.37±0.06△△

Figure 3

Protein expression of vWF in liver tissues A: Photographs of immunofluorescence results (Fluorescence microscopy, ×400); B: Film negatives of Western blot results; C: Grayscale analysis (vWF-to-GAPDH ratio). N: Normal group; 3W: 3-week model group; 6W: 6-week model group; 9W: 9-week model group; X: Xiayuxue Decoction group. The values are represented as x±s. Expressions of vWF protein in different (N, 9W and X) groups were 0.14±0.01, 0.50±0.01 and 0.20±0.02, respectively. **P<0.01, vs normal group;△△P<0.01, vs 9-week model group. vWF: von Willebrand factor; GAPDH: glyceraldehyde-3-phosphate dehydrogenase."

Figure 4

Protein expressions of VEGF, VEGFR2, α-SMA and DAF in liver tissues A: Film negatives of Western blot results; B: Grayscale analysis (ratio to GAPDH). N: Normal group; 3W: 3-week model group; 6W: 6-week model group; 9W: 9-week model group; X: Xiayuxue Decoction group. The values are represented as x±s. Expressions of VEGF protein in different (N, 9W and X) groups were 0.55±0.01, 1.18±0.02 and 0.94±0.03, respectively. Expressions of VEGFR2 protein in different (N, 9W and X) groups were 0.10±0.01, 0.94±0.03 and 0.78±0.03, respectively. Expressions of α-SMA protein in different (N, 9W and X) groups were 0±0, 0.46±0.02 and 0.13±0.01, respectively. Expressions of DAF protein in different (N, 9W and X) groups were 0±0, 0.91±0.01 and 0.09±0.01, respectively. **P<0.01, vs normal group; △△P<0.01, vs 9-week model group. VEGF: vascular endothelial grow factor; VEGFR2: VEGF receptor-2; α-SMA: α-smooth muscle actin; DAF: complement decay-accelerating factor; GAPDH: glyceraldehyde-3-phosphate dehydrogenase."

Figure 5

Activity changes of MMP-2 and MMP-9 in liver tissues A: Film negatives of gelatin zymography; B: Grayscale analysis. N: Normal group; 3W: 3-week model group; 6W: 6-week model group; 9W: 9-week model group; X: Xiayuxue Decoction group. The values of scanning density integrals of activities of MMP-2 and MMP-9 are represented as x±s. Scanning density integrals of activity of MMP-2 in different (N, 9W and X) groups were 0±0, 7.63±0.15 and 0±0, respectively. H=7.62, P<0.05. Scanning density integrals of activity of MMP-9 in different (N, 9W and X) groups were 2.13±0.21, 3.57±0.12 and 2.27±0.25, respectively. **P<0.01, vs normal group; △△P<0.01, vs 9-week model group. MMP: matrix metalloproteinase."

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