Leukotriene B4 Inhibits L-Type Calcium Channels via p38 Signaling Pathway in Vascular Smooth Muscle Cells

Abstract

Background/Aims: Arachidonic acid (AA) and its metabolites are important endogenous lipid messengers. In this study, we test the effect of Leukotriene B₄ (LTB₄), a 5-lipoxygenase metabolite of AA, on L-type calcium channels in A7r5 rat aortic vascular smooth muscle cells. Methods: L-type calcium channel currents were recorded by a patch-clamp technique. The mRNA expression of Ca_V1.2 was determined by Real-time RT-PCR. The protein expression of Ca_V1.2 and p38 activity was determined by Western blot analysis. Results: LTB₄ inhibits L-type channel currents in A7r5 cells in a dose-and time- dependent manner. LTB₄ reduced the mRNA/protein expression of Ca_V1.2 channels in A7r5 cells. BLT1 receptor antagonist LY29311 abrogated the inhibitory effect of LTB₄, while BLT2 receptor antagonist LY255283 had no effect. 5Z-7-oxozeaenol and SB203580, which block TAK1 and p38 kinase respectively, abrogated the LTB₄ inhibitory effect on L-type calcium channels. LTB₄ increased p38 activity in A7r5 cells. Blockage of Src, PI3K, JNK and NF-κB kinase had no effects on LTB₄ inhibition of L-type calcium channel currents in A7r5 cells. Conclusion: We conclude that LTB₄ inhibits L-type calcium channels through BLT1-TAk1-p38 signaling pathway. The LTB₄ inhibitory effect on L-type calcium channels may be involved in its pathological processes such as atherosclerosis.

Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways

“…The MAPK signaling pathway can regulate voltage-gated K + channels in rat coronary arterial smooth muscle cells, which is involved in ethanol-induced coronary artery contraction ( 51 ). Liu et al found that leukotriene B 4 inhibited L-type calcium channels of vascular smooth muscle cells through the p38 signaling pathway ( 52 ). Wu et al found that CXCL13, upregulated by peripheral inflammation, acted on CXCR5 on dorsal root ganglia neurons, and activated p38 MAPK, which increased Na v 1.8 current density and further helped to maintain inflammatory pain ( 53 ).…”

The Kinetics of Lymphatic Dysfunction and Leukocyte Expansion in the Draining Lymph Node during LTB4 Antagonism in a Mouse Model of Lymphedema

“…Through analysis of both NP uptake to the dLNs and in vivo imaging of lymphatic collecting vessel pumping we show that bestatin treatment increases lymphatic function as lymphedema progresses, suggesting that LTB4 mediates the decrease in lymphatic function that occurs during lymphedema development ( Figure 6 A,D). Further study is needed to determine the mechanism through which LTB4 mediates these changes in lymphatic function, whether it is through direct action on collecting lymphatics or through activation of leukocytes and production of various cytokines known to regulate lymphatic contractility [ 42 , 43 , 44 , 45 , 46 ].…”

A new treatment for severe pulmonary arterial hypertension based on an old idea: inhibition of 5‐lipoxygenase

“…19,20 Over the last four decades, the recognized biological actions of LTs have expanded well beyond smooth muscle contraction and chemotaxis, and a sampling of these can be found in references. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] For example, 5-HETE and cysLTs are now recognized to stimulate cell proliferation and have been implicated in the development of colon and prostate cancer; 36,37 LTC 4 appears to be a major trigger of stressinduced oxidative damage. 21 The expression of LT biosynthetic enzymes as well as LT receptors are under the control of transcriptional and epigenetic mechanisms, in particular DNA methylation, and are themselves modulated by a variety of cytokines, growth factors like TGF beta, hormones, and inflammatory mediators.…”

“…Over the last four decades, the recognized biological actions of LTs have expanded well beyond smooth muscle contraction and chemotaxis, and a sampling of these can be found in references 21–37 . For example, 5‐HETE and cysLTs are now recognized to stimulate cell proliferation and have been implicated in the development of colon and prostate cancer; 36 , 37 LTC 4 appears to be a major trigger of stress‐induced oxidative damage 21 …”