Statins Alter Smooth Muscle Cell Accumulation and Collagen Content in Established Atheroma of Watanabe Heritable Hyperlipidemic Rabbits by Yoshihiro Fukumoto,

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Statins Alter Smooth Muscle Cell Accumulation and Collagen Content in Established Atheroma of Watanabe Heritable Hyperlipidemic Rabbits by Yoshihiro Fukumoto, Peter Libby, Elena Rabkin, Christopher C. Hill, Makoto Enomoto, Yasuhiko Hirouchi, Masashi Shiomi, and Masanori Aikawa Circulation Volume 103(7):993-999 February 20, 2001 Copyright © American Heart Association, Inc. All rights reserved.

A, Macrophages and MMP localization in atheroma of WHHL rabbits. A, Macrophages and MMP localization in atheroma of WHHL rabbits. Left, Control group. Intima of WHHL rabbits of control group contains numerous macrophages detected by RAM11. Most macrophages stained positively for MMP-1 (collagenase-1), MMP-3 (stromelysin-1), and MMP-9 (gelatinase-B). Middle, Pravastatin group. Right, Fluvastatin group. Fewer than half of macrophages are MMP-1–, MMP-3–, and MMP-9–positive. Arrowheads indicate internal elastic lamina. Magnification ×100. Scale bar=200 μm. B through D, Quantitative analysis for MMP-1, MMP-3, or MMP-9 expression by macrophages. Data are reported as percentage of MMP-1–, MMP-3–, or MMP-9–positive area within macrophage-containing regions by computer analysis. MMP-1 expression by macrophages was significantly reduced in fluvastatin group compared with control group. MMP-3 and MMP-9 expression by macrophages was significantly reduced in pravastatin and fluvastatin groups compared with control group. Probability values are determined by 1-way ANOVA followed by post hoc test. Bars represent SEM. Mφ indicates macrophages. Yoshihiro Fukumoto et al. Circulation. 2001;103:993-999 Copyright © American Heart Association, Inc. All rights reserved.

A, Localization of SMCs in atheroma of WHHL rabbits of control, pravastatin, and fluvastatin groups. A, Localization of SMCs in atheroma of WHHL rabbits of control, pravastatin, and fluvastatin groups. Left, Control group shows a thin α-smooth muscle actin–positive layer (fibrous cap) in intima. Middle and right, Pravastatin group has more α-smooth muscle actin–positive cells than do control and fluvastatin groups. Arrowhead indicates internal elastic lamina. Magnification ×100. Scale bar=200 μm. B and C, Quantitative analysis for α-smooth muscle actin–positive cells and areas within intima of atheroma. Pravastatin group had significantly more α-smooth muscle actin–positive cells or areas in intima than did control and fluvastatin groups. Probability values are determined by 1-way ANOVA followed by post hoc test. Bars represent SEM. Yoshihiro Fukumoto et al. Circulation. 2001;103:993-999 Copyright © American Heart Association, Inc. All rights reserved.

A, In situ hybridization for procollagen I mRNA and immunohistochemistry for α-smooth muscle actin in atheroma of WHHL rabbits of control, pravastatin, and fluvastatin groups. A, In situ hybridization for procollagen I mRNA and immunohistochemistry for α-smooth muscle actin in atheroma of WHHL rabbits of control, pravastatin, and fluvastatin groups. Top, Procollagen I mRNA: purple signal indicates procollagen I mRNA expression; bottom, α-smooth muscle actin: red signals indicate SMCs. Atheroma of pravastatin group (middle) has more procollagen I mRNA and α-smooth muscle actin–positive cells in intima than control (left) and fluvastatin (right) groups. Magnification ×400. Scale bar=50 μm. B and C, Quantitative analysis for procollagen I mRNA–positive cells within intima (B) and ratio of procollagen mRNA to α-smooth muscle actin–positive cells [C, expressed as Procollagen I mRNA (+) by SMCs]. Pravastatin group had significantly more procollagen mRNA–positive cells than did control or fluvastatin group, but ratio of procollagen mRNA to α-smooth muscle actin–positive cells did not differ among 3 groups. Probability values are calculated from 1-way ANOVA followed by post hoc test. Bars represent SEM. D, Relationships between number of SMCs and procollagen I mRNA–positive cells by in situ hybridization. Data are statistically analyzed by simple regression analysis. Yoshihiro Fukumoto et al. Circulation. 2001;103:993-999 Copyright © American Heart Association, Inc. All rights reserved.

A, Interstitial collagen accumulation in aortic intima detected by picrosirius red polarization. A, Interstitial collagen accumulation in aortic intima detected by picrosirius red polarization. Left, Picrosirius red staining without polarized light. Right, picrosirius red staining under polarized light in same sections as at left. Top, Aorta of control group shows interstitial collagen mainly in adventitia and some in intima and media. Middle and bottom, Pravastatin group shows more interstitial collagen in intima than control and fluvastatin groups. Magnification ×100. Scale bar=200 μm. B, Quantitative analysis of interstitial collagen content detected by picrosirius red polarization. Percent of area positive for sirius red staining within intima was determined by computer analysis. Pravastatin group had significantly more collagen than did control or fluvastatin group. Probability values are determined by 1-way ANOVA followed by post hoc test. Bars represent SEM. Yoshihiro Fukumoto et al. Circulation. 2001;103:993-999 Copyright © American Heart Association, Inc. All rights reserved.

Quantitative analysis of percent TUNEL-positive cells within SMC area in intima. Quantitative analysis of percent TUNEL-positive cells within SMC area in intima. Although there was a trend toward more TUNEL-positive cells within SMC area in fluvastatin group than in control and pravastatin groups, there was no statistically significant difference. Probability values are determined by 1-way ANOVA followed by post hoc test. Bars represent SEM. Yoshihiro Fukumoto et al. Circulation. 2001;103:993-999 Copyright © American Heart Association, Inc. All rights reserved.

Effects of pravastatin and fluvastatin on SMC number measured by MTS assay in cultured rabbit aortic SMCs (A) and cultured human aortic SMCs (B). Effects of pravastatin and fluvastatin on SMC number measured by MTS assay in cultured rabbit aortic SMCs (A) and cultured human aortic SMCs (B). Fluvastatin, but not pravastatin, reduced cell number. Probability values are calculated from 1-way ANOVA followed by post hoc test in each group. Bars represent SEM. Yoshihiro Fukumoto et al. Circulation. 2001;103:993-999 Copyright © American Heart Association, Inc. All rights reserved.

RT-PCR (25 cycles) for rabbit procollagen I mRNA in cultured rabbit aortic SMCs. Pravastatin and fluvastatin incubation for 72 hours in 2 different doses showed no effects on procollagen I mRNA expression by SMCs. RT-PCR (25 cycles) for rabbit procollagen I mRNA in cultured rabbit aortic SMCs. Pravastatin and fluvastatin incubation for 72 hours in 2 different doses showed no effects on procollagen I mRNA expression by SMCs. Yoshihiro Fukumoto et al. Circulation. 2001;103:993-999 Copyright © American Heart Association, Inc. All rights reserved.