Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A₂dependent mechanism

Abstract

Smoking is a major risk factor for endothelial cell injury and subsequent coronary artery disease. Epidemiological studies implicate the phospholipase A2/arachidonic acid cascade in the mechanism by which smoking causes heart disease. However, specific components of cigarette smoke that activate this pathway have not been identified. The purpose of this study was to investigate the effects of polycyclic aromatic hydrocarbons contained in cigarette smoke on phospholipase A2 (PLA2) activity and apoptosis of human coronary artery endothelial cells. 1-methylanthracene (1-MA), phenanthrene (PA), and benzo(a)pyrene (B(a)P) caused significant release of 3H-arachidonate from endothelial cells. 1-MA and PA, but not B(a)P, also caused significant release of 3H-linoleic acid. Release of fatty acids from membrane phospholipids preceded the onset of apoptosis. 3H-arachidonate release and apoptosis induced by 1-MA, B(a)P, and PA were inhibited by methylarachidonoyl-fluorophosphonate, an inhibitor of Groups IV and VI PLA2s. Bromoenol lactone, an inhibitor of Group VI enzymes, inhibited both 3H-arachidonate release and apoptosis induced by 1-MA and PA, but not B(a)P. MJ33, an inhibitor of the acidic calcium-independent PLA2, attenuated 3H-arachidonate release and apoptosis by PA, but not 1-MA or B(a)P. The presence of Groups IV and VI and the acidic iPLA2 in endothelial cells was demonstrated by reverse transcriptase-polymerase chain reaction and Western analysis. These data suggest that 1-MA, B(a)P and PA induce apoptosis of endothelial cells by a mechanism that involves activation of these three distinct isoforms of PLA2.

High-throughput evaluation of aryl hydrocarbon receptor-binding sites selected via chromatin immunoprecipitation-based screening in Hepa-1c1c7 cells stimulated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…This gene encodes cytosolic phospholipase A 2 -α (cPLA 2 -α) playing a central role in the release of arachidonic acid (AA) from sn2 position of membrane phospholipids, and AA metabolism is involved in a number of biological events such as inflammatory and carcinogenic processes. Previous studies revealed that TCDD promoted the release of AA from membranes as a result of its ability to stimulate membrane lipid oxidation and phospholipase A 2 (PLA 2 ) activity (al-Bayati and Stohs, 1991;Forsell et al, 2005;Tithof et al, 1996Tithof et al, , 2002. Therefore, our finding might fill-in the missing link between TCDD stimulation and phospholipase A 2 induction.…”

Cigarette smoke components inhibited intercellular communication and differentiation in human pancreatic ductal epithelial cells

“…3)-formed with either a benzyl (bay region) or alkyl group (bay-like region), were biologically active in the induction of arachidonic acid release, inhibition of GJIC and the activation of mitogen activated protein kinase pathways in a rat liver epithelial cell line with oval cell characteristics. [51][52][53] This structure-activity relationship was also observed in the induction of arachidonic acid release from endothelial cells 54 and the inhibition of GJIC in rat cardiac myocytes. 55 Consistent with these previous observations, 1-methylanthracene, which has a bay-like region, inhibited forskolin-induced GJIC in the H6c7 pancreatic epithelial ductal cells, whereas the linear isomer, 2-methylanthracene, had no effect on GJIC.…”

Endothelial Cell Apoptosis is Responsible for the Formation of Coronary Thrombotic Atherosclerotic Plaques

“…Some studies suggest that patients who die of eroded plaque are often smokers . Recently, a study showed that polycyclic aromatic hydrocarbons found in cigarettes could induce human coronary artery endothelial cell apoptosis (Tithof et al 2002). In addition, despite the lack of evidence that turbulent blood flow directly induces endothelial denudation, an in vivo study suggested that there was a systemic preferential occurrence of apoptosis in the downstream parts of plaques, where low flow and low shear stress prevail (Tricot et al 2000).…”