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| Author(s): |
Julio Beltrame Daleprane
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2011-07-22 |
| Examining board members: |
Dulcineia Saes Parra Abdalla;
Joilson de Oliveira Martins;
Fernando Salvador Moreno;
Eliane Fialho de Oliveira;
Maria Cristina Marcucci Ribeiro
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| Advisor: | Dulcineia Saes Parra Abdalla; Thomas Prates Ong |
| Abstract | |
Propolis is rich in bioactive compounds and widely used in alternative medicine as a preventive agent and/or in therapy. We evaluate the impact of polyphenol-rich fractions of propolis from different origins and types in the angiogenesis process in atherosclerotic lesions. The following samples of propolis were used: Red (red, Alagoas, Brazil), Green (green, Minas Gerais, Brazil) and Brown (brown, Temuco, Chile), with similar concentrations of total polyphenols (~ 32%) but with different profiles of phenolic compounds. Supplementation (250 mg / kg / day) of knockout mice for the LDL receptor (LDLr-/ -) with polyphenols showed that in the initial lesion (LI) protocol supplemented groups had lower (p<0.05) lesion area (Green, 726µm2; Red, 519µm2; Brown 698µm2) compared to control (GC, 1184µm2). In contrast, in the advanced lesions (LA) protocol only the Red group (1082µm2) had smaller lesion area (p<0.05) compared to GC (1598µm2). In both protocols (LI and LA) a reduction (p<0.05 of important genes expression involved in angiogenesis (VEGF, MMP9, PDGF and PECAM) was observed. However, only the group treated with Red propolis was able to increase (p <0.05) the expression of TIMP-1 in the LI protocol. The treatments with all types of propolis inhibited (p<0.05), about 45% the migration of endothelial cells (EC), approximately 55% of tubes formation in aortic rings and almost 50% of formation of new vessels in the chorioallantoic membrane of chick embryo (CAM) compared to the control. While investigating the mechanism of polyphenols action, it was found that polyphenols from Red propolis (PRP) were more effective in modulating the expression of hypoxia-induced factor-1 alpha (HIF-1α) in a dose/time dependent way in EC. Additionally, the polyphenols from red propolis (PRP) reduced the expression of target genes regulated by HIF-11α as GLUT-1, ADM, VEGF besides the VEGF protein secretion in the EC culture medium. In the presence of PRP, the degradation of HIF-11α was exacerbated in RCC4/pVHL cells (renal cell carcinoma with VHL reintroduced); moreover, PRP induced destabilization of HIF-11α accelerating the degradation of this transcription factor by a pVHL-dependent patway. In EC, pVHL was over expressed by inhibition of Cdc42, a repressor of pVHL. We conclude that the polyphenols from Green, Red and Brown propolis have anti-atherogenic potential by inhibiting the expression of angiogenic and inflammatory genes, especially when supplemented at an early stage of the atherosclerotic lesion development. In addition, the polyphenols from Red propolis inhibit the angiogenesis process by increasing the destabilization of HIF-11α via over expression of pVHL-degradation induced by repressed Cdc42 function. (AU) | |