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Inorganic Phosphate (Pi) Signaling in Endothelial Cells: A Molecular Basis for Generation of Endothelial Microvesicles in Uraemic Cardiovascular Disease

Abbasian, Nima ; Bevington, Alan ; Burton, James O ; Herbert, Karl E ; Goodall, Alison H ; Brunskill, Nigel J

International journal of molecular sciences, 2020-10, Vol.21 (19), p.6993 [Periódico revisado por pares]

Switzerland: MDPI AG

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Título:
Inorganic Phosphate (Pi) Signaling in Endothelial Cells: A Molecular Basis for Generation of Endothelial Microvesicles in Uraemic Cardiovascular Disease
Autor: Abbasian, Nima ; Bevington, Alan ; Burton, James O ; Herbert, Karl E ; Goodall, Alison H ; Brunskill, Nigel J
Assuntos: Actin ; Actin Cytoskeleton - metabolism ; Actin Cytoskeleton - pathology ; Antibodies ; Cardiovascular diseases ; Cardiovascular Diseases - enzymology ; Cardiovascular Diseases - pathology ; Catalytic activity ; Cell cycle ; Cell Line, Transformed ; Cell-Derived Microparticles - enzymology ; Cell-Derived Microparticles - pathology ; Confocal microscopy ; Control theory ; Cytoskeletal Proteins - metabolism ; Cytoskeleton ; DAPK-1 ; Depletion ; Disruption ; Endothelial cells ; Endothelial Cells - enzymology ; Endothelial Cells - pathology ; Enzymes ; Feedback loops ; Gene expression ; Humans ; Hyperphosphatemia - enzymology ; Hyperphosphatemia - pathology ; Hypotheses ; inorganic phosphate ; Kidney diseases ; Kinases ; Mammalian cells ; Nanoparticles ; Phosphatase ; Phosphates - metabolism ; Phosphoprotein phosphatase ; Phosphorylation ; Physiological aspects ; PP2A ; Protein Phosphatase 2 - metabolism ; Proteins ; Signal Transduction ; signaling ; Src ; Tropomyosin
É parte de: International journal of molecular sciences, 2020-10, Vol.21 (19), p.6993
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SourceType-Scholarly Journals-1
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Descrição: Hyperphosphataemia increases cardiovascular mortality in patients with kidney disease. Direct effects of high inorganic phosphate (Pi) concentrations have previously been demonstrated on endothelial cells (ECs), including generation of procoagulant endothelial microvesicles (MVs). However, no mechanism directly sensing elevated intracellular Pi has ever been described in mammalian cells. Here, we investigated the hypothesis that direct inhibition by Pi of the phosphoprotein phosphatase PP2A fulfils this sensing role in ECs, culminating in cytoskeleton disruption and MV generation. ECs were treated with control (1 mM [Pi]) vs. high (2.5 mM [Pi]), a condition that drives actin stress fibre depletion and MV generation demonstrated by confocal microscopy of F-actin and NanoSight Nanoparticle tracking, respectively. Immuno-blotting demonstrated that high Pi increased p-Src, p-PP2A-C and p-DAPK-1 and decreased p-TPM-3. Pi at 100 μM directly inhibited PP2A catalytic activity. Inhibition of PP2A enhanced inhibitory phosphorylation of DAPK-1, leading to hypophosphorylation of Tropomyosin-3 at S284 and MV generation. p-Src is known to perform inhibitory phosphorylation on DAPK-1 but also on PP2A-C. However, PP2A-C can itself dephosphorylate (and therefore inhibit) p-Src. The direct inhibition of PP2A-C by Pi is, therefore, amplified by the feedback loop between PP2A-C and p-Src, resulting in further PP2A-C inhibition. These data demonstrated that PP2A/Src acts as a potent sensor and amplifier of Pi signals which can further signal through DAPK-1/Tropomyosin-3 to generate cytoskeleton disruption and generation of potentially pathological MVs.
Editor: Switzerland: MDPI AG
Idioma: Inglês

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Inorganic Phosphate (Pi) Signaling in Endothelial Cells: A Molecular Basis for Generation of Endothelial Microvesicles in Uraemic Cardiovascular Disease

Abbasian, Nima ; Bevington, Alan ; Burton, James O ; Herbert, Karl E ; Goodall, Alison H ; Brunskill, Nigel J

Switzerland: MDPI AG

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