APOPTOSIS AND RELATED PROTEINS IN DIFFERENT STAGES OF HUMAN ATHEROSCLEROTIC PLAQUES

Background-The transition of a fatty streak into an atherosclerotic pl aque is characterized by the appearance of focal and diffuse regions o f cell death. We have investigated the distribution of apoptotic cell death and apoptosis-related proteins in early and advanced atheroscler otic lesions. Methods and Results-Human atherosclerotic plaques were s tudied by whole-mount carotid endarterectomy specimens (n=18). This ap proach allowed comparison of adaptive intimal thickenings, fatty strea ks, and advanced atherosclerotic plaques of the same patient. The fatt y streaks differed from adaptive intimal thickenings by the presence o f BAX (P<0.01), a proapoptotic protein of the BCL-2 family. Both regio ns were composed mainly of smooth muscle cells (SMCs), and macrophage infiltration was low and not different. Apoptosis, as detected by DNA in situ end labeling (terminal deoxynucleotidyl transferase end labeli ng [TUNEL] and in situ nick translation) was not present in these regi ons. Apoptosis of SMCs and macrophages, however, was present in advanc ed atherosclerotic plaques that were present mainly in the carotid sin us. A dense infiltration of macrophages (5.8+/-3% surface area) was pr esent in these advanced atherosclerotic plaques. Cytoplasmic remnants of apoptotic SMCs, enclosed by a cage of thickened basal lamina, were TUNEL negative and remained present in the plaques as matrix vesicles. Conclusions-We conclude that SMCs within human fatty streaks express BAX, which increases the susceptibility of these cells to undergo apop tosis, The localization of these susceptible SMCs in the deep layer of the fatty streaks could be important in our understanding of the tran sition of fatty streaks into atherosclerotic plaques, which are charac terized by regions of cell death. Matrix vesicles are BAX-immunoreacti ve cytoplasmic remnants of fragmented SMCs that can calcify and may be considered the graves of SMCs that have died in the plaques.