H3c

co2h

LTD4 S-cys-gly

Figure 6 Selected steps in leukotriene biosynthesis. The action of phospholipase A2 (PLA2) on phospholipids in cellular membranes releases free arachidonic acid which can be oxidized by the enzyme, 5-lipoxygenase (5-LO), to form 5-hydroperoxy-eicosa-6,8,11,14-tetraenoic acid (5-HPETE). Subsequent conversion of 5-HPETE into leukotriene A4 (LTA4, 4-(3-tetradeca-1(E),3(E),5(Z),8(Z)-tetraenyl-2(S),3(S)-oxiranyl)-butyric acid) is catalyzed by LTA4 synthase. LTA4 can be hydrolyzed by LTA4 hydrolase to form leukotriene B4 (LTB4, 5(S),12(R)-dihydroxy-6(Z),8(E),10(E),14(Z)-eicosatetraenoic acid). Alternatively, LTA4 undergoes enzyme-catalyzed ring opening of the epoxide with the tripeptide, gly-cys-gly, and LTC4 synthase to form the tripeptide adduct, leukotriene C4 (LTC4). LTC4 is converted to the dipeptide adduct, leukotriene D4 (LTD4), by the action of glutamyl transferase.

LDL-mediated cholesterol uptake and HDL-mediated cholesterol efflux in the activated macrophage, and thus plays a key role in the underlying lipid accumulation and activation process.

Activated immune cells such as T cells and mast cells also participate in the inflammatory response within the lesion. The proinflammatory cytokines secreted within the atheroma induce activated T cells to differentiate into Th1 effector cells, producing the cytokine interferon-"/ (IFN-g). IFN-g is a potent activator of macrophages and increases synthesis and secretion of the proinflammatory cytokines TNF-a, interleukin-1 (IL1), and IL6.6 As a result of these combined responses, the underlying pathology and biochemical changes accompanying plaque initiation and progression closely resemble the inflammatory cascade more commonly associated with joint or peripheral tissue injury. However, the accumulation and retention of cholesterol and modified LDL in atherosclerosis are unique characteristics of lesion formation that differentiates atherosclerosis from other inflammatory diseases.

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