CELL COMPOSITION, REPLICATION, AND APOPTOSIS IN ATHEROSCLEROTIC PLAQUES AFTER 6 MONTHS OF CHOLESTEROL WITHDRAWAL

Unstable human atherosclerotic plaques are characterized by a thin fib rous cap that contains few smooth muscle cells (SMCs) and numerous foa m cells of macrophagic origin. Apoptosis of SMCs in the fibrous cap co uld destabilize the plaque and promote plaque rupture. In an experimen tal approach, we have studied apoptotic cell death and related protein s in atherosclerotic plaques of cholesterol-fed rabbits and examined t he effects of cholesterol withdrawal. The induced atherosclerotic plaq ues at the thoracic aorta were composed of both fibromuscular tissue a nd foam cells. The presence of SMCs overlying macrophage accumulation was reminiscent of the structure of human atherosclerotic plaques. The plaques showed signs of cell replication and apoptotic cell death (1. 8 +/- 0.5% terminal deoxynucleotidyl transferase end-labeling [TUNEL]- positive nuclei). Cell replication was confined mostly to the macropha ges, whereas 34% of the TUNEL-labeled cells were SMCs, Both the macrop hages and SMCs in the plaques expressed BAX, a proapoptotic protein of the BCL-2 family. After 6 months of cholesterol withdrawal, the thick ness of the plaques in all localizations of the aorta was unchanged, b ut apoptosis was nearly absent (< 0.1% of nuclei). Moreover, macrophag es disappeared from the plaques, whereas the SMCs that remained presen t lost their lipid accumulation and strongly reduced their BAX express ion, These changes were associated with a reduction of cell replicatio n and increased deposition of fibrillar collagen fibers in the plaques , which pointed to plaque stabilization. In conclusion, the cell compo sition but not the thickness of atherosclerotic plaques was profoundly altered after a 6-month cholesterol withdrawal period. These changes were associated with a strong reduction of cell replication and apopto tic cell death. Moreover, the expression of the proapoptotic factor, B AX, was reduced in the remaining cells, which were mainly SMCs, These findings could help to explain the benefit of lipid-lowering therapy o n plaque stabilization.