Lung Endothelial Ca<sup>2+</sup> and Permeability Response to Platelet-Activating Factor Is Mediated by Acid Sphingomyelinase and Transient Receptor Potential Classical 6

Samapati, Rudi; Yang, Yang; Yin, Jun; Stoerger, Christof; Arenz, Christoph; Dietrich, Alexander; Gudermann, Thomas; Adam, Dieter; Wu, Songwei; Freichel, Marc; Flockerzi, Veit; Uhlig, Stefan; Kuebler, Wolfgang M.

doi:10.1164/rccm.201104-0717oc

Cited by 75 publications

(83 citation statements)

References 47 publications

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“…Recent studies have shown that TRPC6 plays a key role in the onset of the lung ischemia-reperfusion edema (LIRE) as a consequence of endothelial NOX2-dependent ROS, which, in turns, leads to PLCγ activation, DAG kinase inhibition and an increase in submembranal DAG levels [250] . Consistently, PAF-induced lung edema depends upon the activation of acid sphingomyelinase (ASM), which engages TRPC6 to caveolae, thereby resulting in Ca 2+ influx and following increase in endothelial permeability [251] . This process is inhibited by NO donors [251] .…”

Section: Moccia F Et Al Camentioning

confidence: 99%

“…Consistently, PAF-induced lung edema depends upon the activation of acid sphingomyelinase (ASM), which engages TRPC6 to caveolae, thereby resulting in Ca 2+ influx and following increase in endothelial permeability [251] . This process is inhibited by NO donors [251] . TRPC4/5: TRPC4 and TRPC5 form a subfamily with the closest homology with TRPC1 [201] .…”

Section: Moccia F Et Al Camentioning

confidence: 99%

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Update on vascular endothelial Ca²⁺signalling: A tale of ion channels, pumps and transporters

Moccia

Berra‐Romani²,

Tanzi³

2012

WJBC

110

192

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A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca 2+ signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca 2+ levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca 2+ signals, ranging from brief, localized Ca 2+ pulses to prolonged Ca 2+ oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca 2+ signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca 2+ releasing channels, which are located both on the plasma membrane and in a number of intracellular organelles, and Ca 2+ removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca 2+ machinery in vascular ECs under both physiological and pathological conditions.

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Section: Moccia F Et Al Camentioning

confidence: 99%

Section: Moccia F Et Al Camentioning

confidence: 99%

Update on vascular endothelial Ca²⁺signalling: A tale of ion channels, pumps and transporters

Moccia

Berra‐Romani²,

Tanzi³

2012

WJBC

110

192

View full text Add to dashboard Cite

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“…In the lung, dysregulated TRPC6 activity may contribute to pulmonary hypertension (Yu et al, 2009;Smith et al, 2015), allergic airway disease (Sel et al, 2008), and ischemia/ reperfusion-associated edema (Weissmann et al, 2012) or permeability-type barrier failure (Samapati et al, 2012). In the kidney, familial forms of focal segmental glomerulosclerosis are a prominent phenotype that can be caused by gain-of-function mutations in the TRPC6 gene or by TRPC6 overexpression (Winn et al, 2005;Krall et al, 2010).…”

Section: Larixyl Acetate Is a Trpc6 Inhibitormentioning

confidence: 99%

“…TRPC6 is expressed in vascular and airway smooth muscle cells (Welsh et al, 2002;Dietrich et al, 2006;Wang and Zheng, 2011) and contributes to the vasoconstrictor response either by mediating receptorand second messenger-triggered Ca 21 influx, or by depolarizing the smooth muscle cell, resulting in the opening of voltagegated Ca 21 channels. In the pulmonary vascular system, TRPC6 has gained considerable attention from several studies that demonstrated its involvement in hypoxia-induced pulmonary vasoconstriction (HPV) (Weissmann et al, 2006;Fuchs et al, 2011;Tabeling et al, 2015) and idiopathic pulmonary hypertension (Yu et al, 2004(Yu et al, , 2009, and also its role in contributing to lung edema formation (Samapati et al, 2012;Weissmann et al, 2012). In addition, TRPC6 expression in lung macrophages (Finney-Hayward et al, 2010) and in bronchial smooth muscle cells may provide a link between TRPC6 and pathophysiological mechanisms that induce or aggravate chronic or allergic obstructive airway diseases (Sel et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor

et al. 2015

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Classical or canonical transient receptor potential 6 (TRPC6), a nonselective and Ca 21 -permeable cation channel, mediates pathophysiological responses within pulmonary and renal diseases that are still poorly controlled by current medication. Thus, controlling TRPC6 activity may provide a promising and challenging pharmacological approach. Recently identified chemical entities have demonstrated that TRPC6 is pharmacologically targetable. However, isotype-selectivity with regard to its closest relative, TRPC3, is difficult to achieve. Reasoning that balsams, essential oils, or incense materials that are traditionally used for inhalation may contain biologic activities to block TRPC6 activity, we embarked on a natural compound strategy to identify new TRPC6-blocking chemical entities. Within several preparations of plant extracts, a strong TRPC6-inhibitory activity was found in conifer balsams. The biologic activity was associated with nonvolatile resins, but not with essential oils. Of various conifers, the larch balsam was unique in displaying a marked TRPC6-prevalent mode of action. By testing the main constituents of larch resin, we identified larixol and larixyl acetate as blockers of Ca 21 entry and ionic currents through diacylglycerol-or receptor-activated recombinant TRPC6 channels, exhibiting approximately 12-and 5-fold selectivity compared with its closest relatives TRPC3 and TRPC7, respectively. No significant inhibition of more distantly related TRPV or TRPM channels was seen. The potent inhibition of recombinant TRPC6 by larixyl acetate (IC 50 5 0.1-0.6 mM) was confirmed for native TRPC6-like [Ca 21 ] i signals in diacylglycerol-stimulated rat pulmonary artery smooth muscle cells. In isolated mouse lungs, larix-6-yl monoacetate (CAS 4608-49-5; larixyl acetate; 5 mM) prevented acute hypoxiainduced vasoconstriction. We conclude that larch-derived labdane-type diterpenes are TRPC6-selective inhibitors and may represent a starting point for pharmacological TRPC6 modulation within experimental therapies.

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“…Platelet-PMN and endothelial-PMN costimulation may not only be promoted by PMPs, but likewise by PMN microparticles (NMPs), since endotoxin (LPS) can stimulate adherent PMNs to release NMPs that generate platelet-activating factor (PAF), thus causing activation of platelets (172), endothelium (149), and other inflammatory cells. In the air spaces, NMPs may also trigger inflammatory responses and epithelial cell damage, as suggested from their abundance in sputum from patients with cystic fibrosis (136).…”

Section: Potential Detrimental Effects Of Microparticles In Alimentioning

confidence: 99%

Microparticles and acute lung injury

McVey

Tabuchi

Kuebler

2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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125

118

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The pathophysiology of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), is characterized by increased vascular and epithelial permeability, hypercoagulation and hypofibrinolysis, inflammation, and immune modulation. These detrimental changes are orchestrated by cross talk between a complex network of cells, mediators, and signaling pathways. A rapidly growing number of studies have reported the appearance of distinct populations of microparticles (MPs) in both the vascular and alveolar compartments in animal models of ALI/ARDS or respective patient populations, where they may serve as diagnostic and prognostic biomarkers. MPs are small cytosolic vesicles with an intact lipid bilayer that can be released by a variety of vascular, parenchymal, or blood cells and that contain membrane and cytosolic proteins, organelles, lipids, and RNA supplied from and characteristic for their respective parental cells. Owing to this endowment, MPs can effectively interact with other cell types via fusion, receptor-mediated interaction, uptake, or mediator release, thereby acting as intrinsic stimulators, modulators, or even attenuators in a variety of disease processes. This review summarizes current knowledge on the formation and potential functional role of different MPs in inflammatory diseases with a specific focus on ALI/ARDS. ALI has been associated with the formation of MPs from such diverse cellular origins as platelets, neutrophils, monocytes, lymphocytes, red blood cells, and endothelial and epithelial cells. Because of their considerable heterogeneity in terms of origin and functional properties, MPs may contribute via both harmful and beneficial effects to the characteristic pathological features of ALI/ARDS. A better understanding of the formation, function, and relevance of MPs may give rise to new promising therapeutic strategies to modulate coagulation, inflammation, endothelial function, and permeability either through removal or inhibition of “detrimental” MPs or through administration or stimulation of “favorable” MPs.

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Lung Endothelial Ca²⁺ and Permeability Response to Platelet-Activating Factor Is Mediated by Acid Sphingomyelinase and Transient Receptor Potential Classical 6

Cited by 75 publications

References 47 publications

Update on vascular endothelial Ca²⁺signalling: A tale of ion channels, pumps and transporters

Update on vascular endothelial Ca²⁺signalling: A tale of ion channels, pumps and transporters

Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor

Microparticles and acute lung injury

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Lung Endothelial Ca2+ and Permeability Response to Platelet-Activating Factor Is Mediated by Acid Sphingomyelinase and Transient Receptor Potential Classical 6

Cited by 75 publications

References 47 publications

Update on vascular endothelial Ca2+signalling: A tale of ion channels, pumps and transporters

Update on vascular endothelial Ca2+signalling: A tale of ion channels, pumps and transporters

Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor

Microparticles and acute lung injury

Contact Info

Product

Resources

About

Lung Endothelial Ca²⁺ and Permeability Response to Platelet-Activating Factor Is Mediated by Acid Sphingomyelinase and Transient Receptor Potential Classical 6

Update on vascular endothelial Ca²⁺signalling: A tale of ion channels, pumps and transporters

Update on vascular endothelial Ca²⁺signalling: A tale of ion channels, pumps and transporters