The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis
in vivo study by high-resolution magnetic resonance imaging
Roberto Corti, MD*,
Julio I. Osende, MD*,
John T. Fallon, MD, PhD*,
Valentin Fuster, MD, PhD*,
Gabor Mizsei, MSEE*,
Hani Jneid, MD*,
Samuel D. Wright, PhD ,
William F. Chaplin, PhD* and
Juan J. Badimon, PhD*,*
* Cardiovascular Biology Research Laboratory, The Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Merck & Co, Inc., Rathway, New Jersey, USA
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Figure 1 Study design. Magnetic resonance imaging of the abdominal aorta was performed after the atherosclerosis induction period (atherosclerosis [AT] baseline) and at the end of the six-month treatment period. This study design allows each animal to act as its own control.
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Figure 2 Representative magnetic resonance images of the abdominal aorta showing progression in the high-cholesterol diet group (upper panels) and regression in the normal chow diet plus simvastatin plus peroxisomal proliferator-activated receptor-gamma agonist group (lower panels). The raw images at atherosclerosis (AT) baseline (A, F) and at the end of treatment (B, G), as well as the analyzed traced images at AT baseline (C, H) and at the end of treatment (D, I), are shown for the respective treatment groups. The right panels (E, J) show the matched histologic section at the end of treatment.
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Figure 3 Changes in vessel wall dimensions. Line graphs display the vessel wall area (A), lumen area (B), and maximal vessel wall thickness (C) after the induction period (atherosclerois [AT] baseline) and at the end of the six-month treatment period (end of follow-up). Data are displayed as the mean value ± SEM. *p < 0.01 versus baseline. Bar graphs display the percent changes in vessel wall area (D) and maximal vessel wall thickness (E) by comparing the values at the end of treatment with the randomization (AT baseline). p < 0.05 versus high-cholesterol (HC) diet group. #p < 0.05 versus normal chow (ND) diet group.
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Figure 4 Representative histologic sections of the different treatment groups. CME is combined Masson's elastin (trichrome) staining; alpha-actin indicates the staining for smooth muscle cells; and RAM-11 represents the staining for macrophages. HC = high-cholesterol; NC = normal chow; PPAR = perioxisomal proliferator-activated receptor.
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Figure 5 Quantitative analysis of macrophages (A), smooth muscle cells (B), and combined smooth muscle cell/collagen (C) plaque content. Data are expressed as the mean value ± SEM percent area. *p < 0.05 versus high-cholesterol (HC) diet group. #p < 0.05 versus normal chow diet (ND) group. AT = atherosclerosis; PPAR = perioxisomal proliferator-activated receptor.
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Figure 6 (Top) Representative gelatin zymography used for the detection of gelatinolytic activity of the aortic rings. Displayed is the 72-kd band corresponding to pro-matrix metalloproteinase (MMP)-2. No gelatinolytic activity was seen at 92 kd (pro-MMP-9). (Bottom) Quantitative analysis of gelatinolytic activity is displayed as a bar graph. *p < 0.05 versus high-cholesterol (HC) diet group. #p < 0.05 versus normal chow (NC) (ND) diet group. AT = atherosclerosis; PPAR = perioxisomal proliferator-activated receptor.
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