TRANSCRIPTIONAL ACTIVATION OF THE C-HA-RAS PROTOONCOGENE IN VASCULAR SMOOTH MUSCLE CELLS HY BENZO(A)PYRENE

摘要

Cardiovascular disease is a leading cause of mortality in industrialized nations. Several epidemiological studies have suggested that exposure to environmental or occupational chemicals contributes significantly to the development of vascular atherosclerotic lesions (for review, see Ramos et al., 1994). Polycyclic aromatic hydrocarbons have been investigated for many years as contributors to atherogen-esis and carcinogenesis. The finding that an initiating dose of the carcinogen 7,12-dimethylbenz[a]anthracene followed by regular administration of methoxamine, a growth promoter, elicited focal inti-mal smooth muscle cell (SMC) lesions suggests that atherogenesis involves both initiating and promotional components (Majesky et al., 1985). Benzo(a)pyrene (BaP), a persistent environmental contaminant, is a member of this class of compounds known to initiate and/ or promote atherogenesis in experimental animal models (Albert et al., 1977). Recent studies in our laboratory have shown that a single acute dose of 3 mu M BaP to SMCs in vitro induces acquisition of a proliferative phenotype as a function of serial passage (Ou and Ramos, 1992). A comparable response profile can be elicited after repeated administration of BaP in vivo, confirming the physiological relevance of these studies (Ou and Ramos, 1992). To define the molecular basis of the atherogenic response induced by BaP, the expression of genes critical to the regulation of cell proliferation has been examined.