Leukotrines and leukotriene receptors : Potential roles in cardiovascular diseases

University dissertation from Stockholm : Karolinska Institutet, Department of Medical Biochemistry and Biophysics

Abstract: Leukotrienes (LTs) are a family of lipid mediators that are involved in host defense and inflammatory responses. They are synthesized from arachidonic acid through the 5-lipoxygenase (5-LO) pathway, and are divided into two classes, the classical chemoattractant leukotriene B4 (LTB4), and spasmogenic cysteinyl leukotrienes (cys-Us) including LTC4, LTD4 and LTE4. Us exert their actions through stimulation of specific G-protein coupled receptors, and so far two receptors for LTB4, namely BLT1, and BLT2, and two receptors for cys-LTs, namely CysLT1 and CysLT2, have been identified. The present thesis is aimed at investigating the expression and regulation profiles of LT biosynthesis enzymes and receptors in the vascular system in order to define their potential roles in the pathogenesis of cardiovascular diseases. The LT receptor expression was studied in human umbilical vein endothelial cells (HUVECs). We found that HUVECs abundantly express CysLT2 receptor mRNA in vast excess (>4000-fold) of CysLT1 mRNA. Challenge of HUVECs with BAY u9773, a specific CysLT2 agonist, triggered diagnostic Ca2+ transients. LTC4 and LTD4 are equipment agonists, and their actions can be blocked by the dual-receptor antagonist BAY u9773, but not by the CysLT1 - selective antagonist MK571. These data identify CysLT2 as the predominant functional receptor for cys-LTs in endothelial cells. In addition, Lipopolysaccaride (LPS), turner necrosis factor-

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