Artesunate and betulilic acid block lipopolysaccharide-induced angiogenesis and hyperplasia in mice
- Author:
Oian GAO
1
Author Information
- Publication Type:Journal Article
- Keywords: Angiogenesis; Artesunate; Betulilic acid; Hyperplasia; Hypoxia stress; Lipopolysaccharide; Protein nitration
- From: Chinese Pharmaceutical Journal 2015;50(4):330-338
- CountryChina
- Language:Chinese
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Abstract:
OBJECTIVE: To disclose the pathological mechanism of bacterial LPS-induced angiogenesis and hyperplasia in tumorlike hyperplasia and the pharmacological mechanism underlying artesunate and betulilic acid blocking tumor-like hyperplasia. METHODS: The tumor-like hyperplasia models were established for mouse hypodermis and articular synovium using LPS or LPS-containing complete Fround's adjuvant (CFA). The morphological features (inflammatory grades) were described and the histochemical signatures (angiogenesis, hyperplasia, and inflammatory infiltration) were examined. The serial concentrations of nitric oxide (NO), blood oxygen saturation (SpO
2 ) and 3-nitrotyrosine (3NT) were quantitatively determined by biochemical, physiological and immunological procedures, and the expression levels of inducible nitric oxide synthase (iNOS), hypoxia-induced factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) were analyzed by the immunohistochemical method. RESULTS: Both LPS and CFA can lead to the inflammatory phenotypes and abnormal hyperplasia-related microscopic alterations. They enable the elevation of NO, decline of SpO2 , and increase of 3NT (protein nitration). The considerable upregulation of iNOS, HIF-1α and VEGF are accompanied by angiogenesis and hyperplasia. While a NO donor compound replicates such pathogenesis, a NO synthesis inhibitor antagonizes this effect. Artesunate and betulilic acid down-regulate iNOS, HIF-1α and VEGF, decrease NO, and increase SpO2 , thereby leading to the melioration or interruption of aberrant inflammatory angiogenesis and hyperplasia. CONCLUSION: LPS-triggered iNOS overexpression and potent NO burst may represent the direct drivers for angiogenesis and hyperplasia. Due to repression of the pathogenic process of tumor-like hyperplasia, artesunate and betulilic acid possess the prophylactic and therapeutic potentials.
