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HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis

Carmen Bustos, PhD^a, Miguel A. Hernández-Presa, PhD^a, M.ónica Ortego, BS^a, José Tuñón, MD^a, Luis Ortega, MD^*, Fernando Pérez, PhD, Cristina Díaz, MD, Gonzalo Hernández, MD and Jesús Egido, MD^a

^a Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
^* Hospital Clínico, Madrid, Spain
Hospital Gómez Ulla, Universidad Complutense, Madrid, Spain
Parke Davis Spain, Barcelona, Spain

View larger version (13K): [in a new window]   Figure 1 Scheme of the experimental protocol.

View larger version (64K): [in a new window]   Figure 2 Analysis of the vascular lesions. Top, Photomicrographs of representative orcein-stained arterial sections of femoral arteries. A greater neointimal formation (arrows) can be observed in the untreated (A) than in the atorvastatin treated rabbit (B). M, medial layer (magnification x100). Bottom, The atorvastatin-treated group had less severe stenoses estimated both as intima/media ratio (solid bars) or as a percentage of the luminal area occupied by the lesion (open bars). Data are the mean ± SD of seven treated and nine untreated rabbits. *p = 0.001 vs. untreated; **p = 0.038 vs. untreated.

View larger version (115K): [in a new window]   Figure 3 Macrophage detection by immunohistochemistry in arterial sections. Photomicrographs of arterial sections stained with RAM11 antibody, specific for rabbit macrophages. A representative section of each treatment group is shown. A, Nontreated group. B, Atorvastatin-treated group. None of the control animals showed any stain (not shown). Arrow, presence of macrophages (brown) (magnification x400).

View larger version (67K): [in a new window]   Figure 4 MCP-1 detection by immunohistochemistry in arterial sections. Top, Photomicrographs of arterial sections stained with an anti–MCP-1 antibody. Both the neointima and the media showed staining for MCP-1. A representative section of an untreated animal is shown in A and of an atorvastatin treated rabbit in B. Control arteries showed no staining for MCP-1 (not shown) (magnification x400). Bottom, Closed bars represent the mean area stained for MCP-1 in the untreated animals and open bars the mean area stained in treated animals. Data are the mean ± SD of seven treated and nine untreated rabbits. *p < 0.01 vs. untreated and **p < 0.05.

View larger version (142K): [in a new window]   Figure 5 NF-B activity in the lesions. NF-B activity was determined by Southwestern histochemistry in untreated (A), atorvastatin treated (B) and control (C) animals. The binding of the labeled probe is specific since no staining is found with the mutant oligonucleotide (D) (magnification x400). A detail of the localization of the NF-B activity by double staining with anti–macrophage antibody is shown in E and with anti-alpha-actin in F (magnification x1000). The arrows indicate the presence of a nuclei stained for NF-B (blue) and surrounded by a cytoplasm (brown) stained with the antibody specific for macrophages (E) and for VSMC (F).

View larger version (67K): [in a new window]   Figure 6 NF-B and AP-1 activity in the aorta and liver of rabbits. The activation of NF-B (left) and AP-1 (right) was determined in the aorta (bottom) and liver (top) of the rabbits by electrophoretic mobility shift assay (EMSA). Cellular extracts obtained from the aorta and liver of the animals from the same group were pooled. (+) positive control with Hela nuclear extracts and (–) negative control without cellular extract. Representative of two experiments done.

View larger version (46K): [in a new window]   Figure 7 Atorvastatin modulation of NF-B activity and MCP-1 expression in VSMC. Vascular smooth muscle cells were growth-arrested by serum deprivation for 48 h and then preincubated with 10–7 mol/L atorvastatin for 1 h before the addition of 100 U/mL of TNF. Cells were then cultured for 6 h to study MCP-1 expression by Northern blot and for 1 h to determine NF-B activity by EMSA. G3PDH mRNA expression was used to normalize the MCP-1 expression. A representative blot of three experiments done is shown.