Differential leukotriene constrictor responses in human atherosclerotic coronary arteries

Background-Leukotrienes are a class of biologically active lipids that have potent effects on the heart. To assess their role in coronary artery disease, we compared the contractile responses of leukotriene C-4 (LTC4) and leukotriene D-4 (LTD,) and their binding activity in both atherosclerotic and nonatherosclerotic human coronary arteries. We also studied expression of the enzymes that control their formation to understand how the 5-lipoxygenase (5-LO) pathway is activated in the coronary arteries. Methods and Results-The capacity of leukotrienes to affect coronary vessel tone and the influence of atherosclerosis was tested in organ baths. Leukotriene receptors were examined by autoradiography, and antibody binding to the various enzymes responsible for their formation was assessed by use of immunocytochemistry. Nonatherosclerotic coronary artery ring segments were unresponsive to LTC4 and LTD4. In contrast, LTC4 and LTD4 induced concentration-dependent contractions in atherosclerotic coronary arteries. Specific [H-3]-LTC4 but not LTD4 binding to atherosclerotic coronary artery was evident, with no evidence of specific binding of [H-3]-leukotrienes to nonatherosclerotic coronary artery. High-resolution autoradiography identified specific [H-3]-LTC4 binding sites to smooth muscle cell and to regions of intimal proliferation and plaque. Cells showing positive antibody binding to 5-LO, FLAP (5-lipoxygenase activating protein), and leukotriene A(4) hydrolase were also present in the coronary arteries and had a similar distribution to macrophages. Conclusions-Atherosclerosis is associated with a specific leukotriene receptor(s) capable of inducing hyperreactivity of human epicardial coronary arteries in response to LTC4 and LTD4.