leukotriene-c4 and Cardiovascular-Diseases

Cysteinyl-leukotrienes (cysteinyl-LTs), that is, LTC4, LTD4, and LTE4, trigger contractile and inflammatory responses through the specific interaction with G protein-coupled receptors (GPCRs) belonging to the purine receptor cluster of the rhodopsin family, and identified as CysLT receptors (CysLTRs). Cysteinyl-LTs have a clear role in pathophysiological conditions such as asthma and allergic rhinitis (AR), and have been implicated in other inflammatory conditions including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. Molecular cloning of human CysLT1R and CysLT2R subtypes has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Interestingly, recent data provide evidence for the immunomodulation of CysLTR expression, the existence of additional receptor subtypes, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Furthermore, genetic variants have been identified for the CysLTRs that may interact to confer risk for atopy. Finally, a crosstalk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize and attempt to integrate recent data derived from studies on the molecular pharmacology and pharmacogenetics of CysLTRs, and will consider the therapeutic opportunities arising from the new roles suggested for cysteinyl-LTs and their receptors.

Topics: Adult; Animals; Asthma; Cardiovascular Diseases; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Membrane Proteins; Pharmacogenetics; Receptors, Leukotriene; Receptors, Purinergic; Recombinant Proteins; Rhinitis, Allergic, Seasonal; SRS-A; Tissue Distribution

Leukotrienes are potent inflammatory mediators synthesized locally within the cardiovascular system through the 5-lipoxygenase pathway of arachidonic acid metabolism. The leukotrienes, consisting of dihydroxy leukotriene LTB4 and the cysteinyl leukotrienes LTC4, LTD4 and LTE4, act by targeting cell surface receptors expressed on inflammatory cells and on structural cells of vessel walls. LTB, induces leukocyte activation and chemotaxis via high- and low-affinity receptor subtypes (BLT1 and BLT2), respectively. Recently, BLT, receptors were found on human vascular smooth muscle cells, inducing their migration and proliferation. Cysteinyl leukotrienes are vasoconstrictors and induce endothelium-dependent vascular responses through the CysLT, and CysLT2 receptor subtypes. There is also pharmacological evidence for the existence of further CysLT receptor subtypes. Taken together, experimental and genetic studies suggest a major role of leukotrienes in atherosclerosis and in its ischemic complications such as acute coronary syndromes and stroke. Furthermore, the effects on vascular smooth muscle cells suggest a role in the vascular remodeling observed after coronary angioplasty, as well as in aortic aneurysm. Further experimental and clinical studies are needed to determine the potential of therapeutic strategies targeting the leukotriene pathway in cardiovascular disease.

Topics: Angioplasty, Balloon, Coronary; Animals; Aortic Aneurysm; Arachidonic Acid; Atherosclerosis; Cardiovascular Diseases; Cell Movement; Coronary Restenosis; Disease Models, Animal; Guinea Pigs; Humans; Hypertension; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Mice; Muscle, Smooth, Vascular; Rats; Receptors, Leukotriene; Stroke

Formation of eicosanoids is a special mode of cell communication whereby production of eicosanoids by mixed cell populations differs from that expected from each individual cell. Transcellular biosynthesis of leukotriene C4 occurs via transfer of the reactive intermediate leukotriene A4 from neutrophils to vicinal acceptor cells devoid of 5-lipoxygenase activity such as platelets or vascular cells. Evidence for the in vivo relevance of transcellular eicosanoid metabolism results from experiments using the isolated beating rabbit heart perfused with activated neutrophils. The resultant leukotriene C4 synthesis is timely related to the pressor response of the coronary arteries and inflammatory damage of the heart by edema formation and neutrophil infiltration into the organ. Blockade of leukotriene C4 synthesis by 5-lipoxygenase inhibitors or leukotriene C4 actions by respective receptor antagonists facilitated significant protective effects. Further confirmation of the potential role of LTC4 in myocardial ischemia comes from in vivo studies in the rabbit.

Topics: Animals; Arachidonate 5-Lipoxygenase; Blood Platelets; Blood Pressure; Brain Ischemia; Cardiovascular Diseases; Cell Communication; Eicosanoids; Endothelium, Vascular; Humans; Leukotriene A4; Leukotriene C4; Muscle, Smooth, Vascular; Myocardial Ischemia; Neutrophils; Rabbits