© 1998 American Heart Association, Inc.
Original Contributions |
Lipid Lowering Promotes Accumulation of Mature Smooth Muscle Cells Expressing Smooth Muscle Myosin Heavy Chain Isoforms in Rabbit Atheroma
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-232).
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Departments of Medicine (M.A., S.J.V., P.L.) and Pathology (E.R., H.S., F.J.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, and the Second Department of Internal Medicine, Gunma University School of Medicine (R.N.), Gunma, Japan.
Correspondence to Dr Peter Libby, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Abstract—Smooth
muscle cells (SMCs) in the atherosclerotic intima characteristically
differ from those in the arterial media, for example, by
reduced expression of SMC differentiation/maturation markers such as
smooth muscle myosin heavy chain isoforms (SM1 and SM2). This study
tested the hypothesis that lipid lowering promotes maturation of
intimal SMCs in 33 rabbits subjected to balloon injury and
cholesterol feeding (0.3%) for 4 months (Baseline group,
n=15); some of which then were switched to a
low-cholesterol diet for 8 months (Low group at 8 months,
n=3) or 16 months (Low group at 16 months, n=10). The remaining rabbits
continued to consume a high-cholesterol diet for 16 months
(High group, n=5). We monitored SMC phenotype by expression of
immunoreactive 
-smooth muscle actin, SM1, and SM2. -Actin is an
early marker, and SM1 and SM2 are late markers for SMC
differentiation/maturation. Only fully differentiated or mature SMCs
express SM2. Data are reported as the percentage of the
-actin-positive intimal area occupied by smooth muscle
myosin–positive SMCs determined by color image analysis of
immunostained sections. Levels of SM1 and SM2, highly
expressed by SMCs in the normal aortic media (n=5) decreased in the
aortic intima of the Baseline and High groups, indicating a less mature
phenotype. In contrast, SM1 and SM2 increased in the Low (16
months) group, indicating that intimal SMCs exhibit a more mature
phenotype after lipid lowering. Electron microscopy also showed
the presence of mature intimal SMCs with abundant myofilaments.
Furthermore, lipid lowering reduced levels of platelet-derived
growth factor-B in the arterial intima, a factor known to
suppress smooth muscle myosin expression. These data demonstrate that
lipid lowering favors accumulation of mature SMCs in the
atherosclerotic intima in association with reduced levels of
platelet-derived growth factor-B expression. Intimal SMCs in the
Low group also displayed reduced expression of matrix
metalloproteinases-3 and -9 compared with the Baseline and High groups.
These findings shed new light on the effects of lipid lowering at the
level of the vascular wall, which may influence the biology of the
atheroma.
Key Words: atherosclerosis • smooth muscle cell • differentiation • hypercholesterolemia • lipid lowering
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