Cysteinyl leukotriene signaling through perinuclear CysLT1 receptors on vascular smooth muscle cells transduces nuclear calcium signaling and alterations of gene expression
Authors:
Open Access
- 20 April 2012
- journal article
- research article
- Published by Springer Nature in Journal of Molecular Medicine
- Vol. 90 (10) , 1223-1231
Abstract
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 CysLT1 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 CysLT1 receptor and significantly enhanced the changes in intracellular calcium induced by leukotriene C4 (LTC4). In these cells, the CysLT1 receptor exhibited a perinuclear expression, and LTC4 stimulation predominantly enhanced nuclear calcium increase, which was significantly inhibited by the CysLT1 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 LTC4, a 5-fold increase in mRNA levels for plasminogen activator inhibitor (PAI)-2. The LTC4-induced increase in PAI-2 expression was confirmed by real-time quantitative PCR and ELISA and was inhibited by the CysLT1 receptor antagonist MK-571 and by calcium chelators. In summary, pro-inflammatory stimulation of vascular SMCs upregulated a perinuclear CysLT1 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 CysLT1 receptor signaling in vascular SMCs inducing gene expression patterns associated with atherosclerosis.Keywords
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