Atorvastatin inhibits inflammatory angiogenesis in mice through down regulation of VEGF, TNF-alpha and TGF-beta1.
While compelling evidence indicates beneficial effects of statins on inflammatory processes, besides their cholesterol-lowering activities, the actions on angiogenesis are less clear-cut. Our aim was to investigate the effects of atorvastatin on key components of inflammatory angiogenesis in the murine sponge model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss mice. Atorvastatin (0.6, 3 mg/kg/day) was given orally for 8 days in drinking water. The implants collected at day 9 postimplantation were processed for the assessment of hemoglobin, myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Atorvastatin treatment resulted in significant decrease in sponge vascularization (Hb content) and in VEGF levels at both doses. Neutrophil influx (MPO activity) was not affected by the compound whereas macrophage recruitment (NAG activity) was inhibited, suggesting a degree of selectivity by atorvastatin for this cell population. The level of CCL2 (MCP1-JE) was decreased only with 0.6 mg/kg. Atorvastatin was also able to reduce collagen deposition and the levels of transforming growth factor (TGF-beta1) intraimplant, dose-dependently. The inhibitory function of atorvastatin on multiple parameters of main components of inflammatory angiogenesis revealed in this study is clearly associated with the modulatory effects of HMG-CoA reductase on VEGF, TNF-alpha and TGF-beta1 production.
Araújo
F A
FA
Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais-UFMG, Avenida Antônio Carlos, 6627, Cep: 31.270-901 Belo Horizonte, Brazil.
Rocha
M A
MA
Mendes
J B
JB
Andrade
S P
SP
D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000069059:Atorvastatin