Mechanisms of toxicant-induced vascular cell injury: Role of phospholipase A(2) enzymes.

摘要

Polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants resulting from incomplete combustion of organic matter, emission sources, automobile exhausts, cigarette smoke (CS), residential wood, or coal combustion.; CS has been implicated as a major risk factor in atherosclerotic heart disease through a mechanism that involves endothelial cell (EC) injury and apoptosis or programmed cell death. Little is known about the specific components of CS responsible for this effect or the mechanisms by which CS induces EC injury and progression of atherosclerosis. However, the phospholipase A ₂/arachidonic acid (PLA₂/AA) pathway might be involved in SC-induced EC injury.; In this research, the long-range goal was to understand the role of several PAHs found in the environment and CS in the EC and smooth muscle cells (SMC) injury. The hypothesis to be tested is that EC and SMC PAH-induced apoptosis is mediated by PLA₂/AA pathway.; The objectives of this research were (1) to evaluate the effects on EC injury of different PAHs present in high concentration in both Chattanooga creek and CS. (2) to test the molecular mechanisms by which PAHs induce such effect. (3) to test the effect of PAHs on SMC in vitro and to characterize the role of different PLA₂ isoforms in such effect.; In this research, we found that Chattanooga creek contains extremely high levels of 11 out of 16 EPA priority PAHs. The levels range from 10,625 mg/kg soil (phenanthrene) to 97 mg/kg soil for fluorene compounds. Six out of the 11 compounds studied, found in the creek or in CS, activate the AA cascade and induce apoptosis of EC. Three of the 11 PAHs cause these effects by activating and increasing the expression of two different isoforms of PLA ₂; the Group VIβ and the Group IVγ enzymes. Furthermore, three out of 11 activate and increase expression of only the Group IVγ PLA₂. PLA₂ activation and release of AA is associated with an increase in apoptosis as measured by histone fragmentation and cleavage of PARP. From these results, we hypothesize that the water solubility as well as the molecular structures of the compounds play important roles in the effects of PAHs on EC PLA₂ activation and apoptosis.; We also found that 8 PAHs present in high concentrations in CS and in urban pollution induce EC apoptosis by a mechanism that involves PLA ₂-mediated activation of JNKs, p-38, and caspases-8, -9, and -3. PAHs induce phosphorylation of JNK-1, JNK-2, p-38, and the transcription factor c-Jun, resulting in apoptosis in EC. (Abstract shortened by UMI.)