Leukotrienes are pro-inflammatory mediators that are locally produced in coronary
atherosclerotic plaques. The response induced by cysteinyl
leukotrienes (CysLT) in human coronary arteries may be altered under pathological conditions, such as
atherosclerosis. The aim of the present study was to elucidate
cysteinyl leukotriene signaling in vascular smooth muscle cells (SMCs) and the effects of
inflammation on this process. Immunohistochemical analysis of human
carotid endarterectomy samples revealed that the CysLT(1)
leukotriene receptor was expressed in areas that also stained positive for α-smooth muscle actin. In human coronary artery smooth muscle cells,
lipopolysaccharide significantly upregulated the
CysLT(1) receptor and significantly enhanced the changes in intracellular
calcium induced by
leukotriene C(4) (LTC(4)). In these cells, the
CysLT(1) receptor exhibited a perinuclear expression, and LTC(4) stimulation predominantly enhanced nuclear
calcium increase, which was significantly inhibited by the
CysLT(1) receptor antagonist
MK-571. Microarray analysis revealed, among a number of significantly upregulated genes after 24 h stimulation of human coronary artery smooth muscle cells with LTC(4), a 5-fold increase in
mRNA levels for
plasminogen activator inhibitor (PAI)-2. The LTC(4)-induced increase in
PAI-2 expression was confirmed by real-time quantitative PCR and ELISA and was inhibited by the
CysLT(1) receptor antagonist
MK-571 and by
calcium chelators. In summary, pro-inflammatory stimulation of vascular SMCs upregulated a perinuclear
CysLT(1) receptor expression coupled to nuclear calcium signaling and changes in gene expression, such as upregulation of
PAI-2. Taken together, these findings suggest a role of nuclear
CysLT(1) receptor signaling in vascular SMCs inducing gene expression patterns associated with
atherosclerosis.