Ramos K S, Bowes R C, Ou X, Weber T J
Department of Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station 77843-4466.
J Toxicol Environ Health. 1994 Dec;43(4):419-40. doi: 10.1080/15287399409531932.
Over the past several decades emphasis has been given to the elucidation of mechanisms involved in the onset and progression of cardiovascular disorders. Stroke, hypertension, and atherosclerosis continue to rank as primary causes of death in the western world. In the case of atherosclerosis, the preferential localization of atheroma to large- and medium-sized blood vessels and the sequence of events leading to plaque development have been well defined. Damage to luminal endothelial and/or medial smooth muscle cells, migration of inflammatory cells, diffusion or local delivery of mediators within the vessel wall, proliferation of vascular smooth muscle cells, and cellular accumulation of lipids are now recognized as hallmarks of the pathologic process. Although these events have been established with a fair degree of certainty, the mechanisms responsible for initiation of the atherosclerotic process are not yet completely understood. Environmental chemicals have come under increasing scrutiny as evidence continues to accumulate suggesting that toxic insult plays an important role in the initiation and/or progression of atherosclerotic disorders. This review focuses on various aspects of xenobiotic-induced vascular injury with emphasis on the toxic effects of allylamine and benzo[a]pyrene in smooth muscle cells, the primary cellular component of atherosclerotic lesions. Both of these chemicals modulate growth and differentiation programs in aortic smooth muscle cells and have been implicated in the development of atherosclerotic-like lesions in laboratory animals. The major findings from recent studies examining the cellular and molecular basis of toxicant-induced phenotypic modulation of vascular smooth muscle cells to a proliferative state and the role of oxidative metabolism, phospholipid turnover, protein kinase C, ras-related signal transduction, and matrix interactions in the vasculotoxic response to allylamine and benzo[a]pyrene are discussed.
在过去几十年中，人们一直致力于阐明心血管疾病发生和发展所涉及的机制。中风、高血压和动脉粥样硬化仍然是西方世界的主要死因。就动脉粥样硬化而言，动脉粥样瘤在大中型血管中的优先定位以及导致斑块形成的一系列事件已得到明确界定。管腔内皮细胞和/或中层平滑肌细胞的损伤、炎症细胞的迁移、血管壁内介质的扩散或局部递送、血管平滑肌细胞的增殖以及脂质的细胞积聚，现在被认为是病理过程的标志。尽管这些事件已在相当程度上得到确定，但动脉粥样硬化过程起始的机制尚未完全了解。随着越来越多的证据表明毒性损伤在动脉粥样硬化疾病的起始和/或发展中起重要作用，环境化学物质受到了越来越多的关注。本综述聚焦于外源性物质诱导的血管损伤的各个方面，重点关注烯丙胺和苯并[a]芘对平滑肌细胞（动脉粥样硬化病变的主要细胞成分）的毒性作用。这两种化学物质都调节主动脉平滑肌细胞的生长和分化程序，并与实验动物中动脉粥样硬化样病变的发展有关。本文讨论了最近研究的主要发现，这些研究探讨了毒物诱导血管平滑肌细胞表型调节至增殖状态的细胞和分子基础，以及氧化代谢、磷脂周转、蛋白激酶C、ras相关信号转导和基质相互作用在对烯丙胺和苯并[a]芘的血管毒性反应中的作用。
