LTC4SLeukotriene C4 Synthase
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The role of LTC4S has been investigated in the Muscatine study [92] which demonstrated the associations between coronary artery calcium (CAC) and intima/media thickness (IMT) (indices strongly associated with the amount of coronary atherosclerotic plaque) [93, 94] and the (-444) A > C promoter polymorphism of LTC4S in woman, but not in men.
A significant increase in LTC4S and [CysLT.sub.1]R gene expression was observed in a model of [ApoE.sup.-/-] atherosclerotic heart disease subjected to hypoxic stress [54] compare to wild-type control mice.
In detail, the rank of affinity toward [CysLT.sub.1]R is LTD4 > LTC4 > LTE4 whereas for [CysT.sub.2]R is LTC4 = LTD4 >> LTE4 [9, 10].
The multidrug resistance protein-1 (MRP1) was suggested as a mediator of the effect of LTC4 on atherosclerosis.
An in vitro study showed a proatherogenic mechanism mediated by MRP1 and LTC4: pharmacological inhibition of MRP1 and [CysLT.sub.1]R by MK571 and montelukast, respectively, reduced angiotensin II-induced ROS release in vascular SMCs [88].
CysLT receptor subtypes are expressed in diseased human arteries, and hyperreactivity of atherosclerotic coronary arteries in response to LTC4 was found to be associated with the expression of CysLT receptors [89].
In contrast, LTD4 and LTC4 induced contraction in atherosclerotic coronary arteries which is inhibited by the [CysLT.sub.1]R antagonist ICI198615 [89, 106] suggesting increased sensitivity to CysLTs during atherogenesis, probably due to an increased in the number of the binding site for LTD4 and LTC4 in atherosclerotic vessels [89, 105].
Recently, an in vitro study [91] showed that LTC4 and LTD4 induce robust calcium influx in human umbilical vein endothelial cells (HUVECs), which was significantly inhibited by both Rho kinase inhibitor (Y27632) and [CysLT.sub.2]R antagonist (BayCysLT2), but not by [CysLT.sub.1]R antagonist (MK571), suggesting that contraction of EC, induced by LTD4, was mediated only by [CysLT.sub.2]R [91].
Furthermore, LTC4 and LTD4 increased the expression of the adhesion molecule P-selectin in human ECs [45,109].
As reported for atherosclerosis, MRP1 seems to mediate, at least in part, the cardiac effects of LTC4. A recent study has suggested an important role of MRP1 on intracellular redox homeostasis and myocardial performance [51].
LTC4 and LTD4 are easily metabolized in the following stages, while LTE4 is released into the urine in a stable manner; it is therefore suitable for use as a biomarker [24].