Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation

Wang, Ziqing; Cai, Ming; Tay, Li Wei Rachel; Zhang, Feng; Wu, Ping; Huynh, Anh; Cao, Xiumei; Peng, Junmin; Milewicz, Dianna M.; Du, Guangwei

doi:10.1096/fj.201800390rr

Cited by 13 publications

(4 citation statements)

References 60 publications

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“…Similarly, we obtained the same results using the in vitro chemical inhibition of PLD2 in HUVECs. PLD2 is a lipid signal transduction enzyme whose classical function is to catalyze the hydrolysis of PC to generate the signal molecule PA [39]. We next tested whether the PA increase was positively related to STAT3 phosphorylation, con rming this hypothesis.…”

Section: Discussionmentioning

confidence: 93%

Deletion of PLD2 Alleviates LPS Induced Acute Lung Injury by Inhibiting STAT3 Phosphorylation and Regulating Endothelial Tight Junctions

Qian

Fei

et al. 2022

Preprint

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Background: Acute respiratory distress syndrome (ARDS) is the leading cause of acute respiratory failure. Endothelial cell damage and increased permeability are critical in developing acute lung injury (ALI). Phospholipase D2 (PLD2) and its metabolite phosphatidic acid (PA) regulate many physiological activities in cells, disrupting cell barrier integrity. However, the exact mechanism remains unexplored. Therefore, we elucidated the role and action mechanism of PLD2 in lipopolysaccharide (LPS)-induced endothelial cell integrity.Methods: We used wild-type (WT) and PLD2 knockout (PLD2-/-) mouse models of LPS-induced ALI. Altered pulmonary endothelial permeability was assessed using histopathological analysis. The relative permeability of the pulmonary vascular endothelial cell culture model was assessed using transwell chamber assays for FITC-dextran and TEER transcellular resistance. The PA content, a downstream product of PLD2, was detected using ELISA, and the mRNA expression of tight junction proteins was detected by real-time quantitative polymerase chain reaction (RT-PCR). Changes in tight junction protein levels and STAT3 pathway phosphorylation, a critical endothelial barrier component, were assessed using immunofluorescence and western blotting analyses in vivo and in vitro.Results: PLD2-/- could significantly improve the histopathological changes, lung wet-dry ratio, and endothelial cell permeability in LPS-induced ALI mice. Simultaneously, PLD2-/- could reduce PA-induced STAT3 phosphorylation, resulting in reduced endothelial tight junction degradation.Conclusion: Loss or inhibition of PLD2 significantly inhibits tight junction injury and alleviates lung injury. LPS-induced PA production leads to STAT3 pathway phosphorylation and tight junction protein targeting, resulting in increased barrier permeability. Collectively, PA is crucial in ARDS pathogenesis.

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Section: Discussionmentioning

confidence: 93%

Deletion of PLD2 Alleviates LPS Induced Acute Lung Injury by Inhibiting STAT3 Phosphorylation and Regulating Endothelial Tight Junctions

Qian

Fei

et al. 2022

Preprint

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“…50 Moreover, in symptomatic plaques, enhanced FFAR2-FAM3C and PLD2-ARF1 interactions favored EREG + monocytes to promote monocyte adhesion, macrophage phagocytosis, EC hyperpermeability, and SMC migration. 51,52 Of course, there were still many crucial ligand-receptor pairs in B cell, DC, neutrophil, NK cell, EC, and SMC subtypes that might be responsible for cerebrovascular events and deserved further exploration (Figures S12 and S13). In conclusion, the heterogeneity within carotid atherosclerosis was comprehensively dissected, with plaque-specific or cerebrovascular event–promoting cell subtypes identified, core genes and cellular mechanisms explored, and an unprecedented ultra-high-precision cellular landscape of the atherosclerotic microenvironment depicted (Figure 7E).…”

Section: Resultsmentioning

confidence: 99%

Single-Cell Transcriptomics Reveals Crucial Cell Subsets and Functional Heterogeneity Associated With Carotid Atherosclerosis and Cerebrovascular Events

Tan,

Liang,

Yang

et al. 2023

ATVB

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BACKGROUND: Carotid atherosclerosis is a chronic inflammatory disorder and is responsible for the vast majority of ischemic strokes. Inappropriate innate and adaptive immune responses synergize with malfunctional vascular wall cells to cause atherosclerotic lesions. Yet, functional characteristics of specific immune and endothelial cell subsets associated with atherosclerosis and cerebrovascular events are poorly understood. METHODS: Here, using single-cell RNA sequencing, the unprecedentedly largest data set from 20 patients’ carotid artery plaques and paired peripheral blood mononuclear cells was generated, with which an ultra-high-precision cellular landscape of the atherosclerotic microenvironment involving 372 070 cells was depicted. RESULTS: Compared with peripheral blood mononuclear cells, 3 plaque-specific T-cell subsets exhibiting proatherogenic features of both activation and exhaustion were identified. Strikingly, usually antiatherogenic, CD4 + FOXP3 + regulatory T cells from plaques of patients with symptomatic disease acquired proinflammatory properties by probably converting to T helper 17 and T helper 9 cells, while CD4 + NR4A1 + /C0 and CD8 + SLC4A10 + T cells related to cerebrovascular events possessed atherogenic attributes including proinflammation, polarization, and exhaustion. In addition, monocyte-macrophage dynamics dominated innate immune response. Two plaque-specific monocyte subsets performed diametrically opposed functions, EREG + monocytes promoted cerebrovascular events while C3 + monocytes are anti-inflammatory. Similarly, IGF1 + and HS3ST2 + macrophages with classical proinflammatory M1 macrophage features were annotated and contributed to cerebrovascular events. Moreover, SULF1 + (sulfatase-1) endothelial cells were also found to participate in cerebrovascular events through affecting plaque vulnerability. CONCLUSIONS: This compendium of single-cell transcriptome data provides valuable insights into the cellular heterogeneity of the atherosclerotic microenvironment and the development of more precise cardiovascular immunotherapies.

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“…PLD activation in cells results in generation of PA, which is recognized as a key lipid secondmessenger involved in a number of cellular responses such as proliferation (29,30), vesicular trafficking (31,32), cytoskeletal reorganization (33)(34)(35), , activation of NADPH oxidase (36), secretion of pro-inflammatory cytokines (55), neo-intima formation (56), and endothelial barrier function [58]. Studies describing the role of PLD in regulating endothelial permeability were carried out in vitro using either bovine pulmonary artery (57) or human umbilical vein ECs (58).…”

Section: Discussionmentioning

confidence: 99%

“…Tyrosine phosphorylation of VEcadherin at 658 by c-Src, facilitates VE-cadherin internalization in a β-arrestin dependent manner (3), and the internalized VE-cadherin enters endosomal compartments and is either recycled to the plasma membrane or subjected to degradation (68). Recent studies have shown that spatiotemporally generated PA from PLD2 acts as signaling platforms for MT1-MMP surface trafficking and lung metastasis of breast cancer cells (69), ERK signaling in cancer cells (47), podosome formation (70), and recruitment of IQGAP1 associated with neo-intima formation (56). In addition to PLD2, PLD1 mediated PA generation in microdomains promotes vesicular fusion to the plasma membrane during exocytosis of large dense-core granules [70]; however, a role for PA confinement in microdomains in VE-cadherin redistribution to AJs is unknown.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation

Ramchandran

Shaaya

et al. 2020

Journal of Biological Chemistry

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Increased permeability of vascular lung tissues is a hallmark of acute lung injury and is often caused by edemagenic insults resulting in inflammation. Vascular endothelial (VE)-cadherin undergoes internalization in response to inflammatory stimuli and is recycled at cell adhesion junctions during endothelial barrier re-establishment. Here, we hypothesized that phospholipase D (PLD)-generated phosphatidic acid (PA) signaling regulates VE-cadherin recycling and promotes endothelial barrier recovery by dephosphorylating VE-cadherin. Genetic deletion of PLD2 impaired recovery from protease-activated receptor-1–activating peptide (PAR-1–AP)-induced lung vascular permeability and potentiated inflammation in vivo. In human lung microvascular endothelial cells (HLMVECs), inhibition or deletion of PLD2, but not of PLD1, delayed endothelial barrier recovery after thrombin stimulation. Thrombin stimulation of HLMVECs increased co-localization of PLD2-generated PA and VE-cadherin at cell-cell adhesion junctions. Inhibition of PLD2 activity resulted in prolonged phosphorylation of Tyr-658 in VE-cadherin during the recovery phase 3 h post-thrombin challenge. Immunoprecipitation experiments revealed that after HLMVECs are thrombin stimulated, PLD2, VE-cadherin, and protein-tyrosine phosphatase nonreceptor type 14 (PTPN14), a PLD2-dependent protein-tyrosine phosphatase, strongly associate with each other. PTPN14 depletion delayed VE-cadherin dephosphorylation, reannealing of adherens junctions, and barrier function recovery. PLD2 inhibition attenuated PTPN14 activity and reversed PTPN14-dependent VE-cadherin dephosphorylation after thrombin stimulation. Our findings indicate that PLD2 promotes PTPN14-mediated dephosphorylation of VE-cadherin and that redistribution of VE-cadherin at adherens junctions is essential for recovery of endothelial barrier function after an edemagenic insult.

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Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation

Cited by 13 publications

References 60 publications

Deletion of PLD2 Alleviates LPS Induced Acute Lung Injury by Inhibiting STAT3 Phosphorylation and Regulating Endothelial Tight Junctions

Deletion of PLD2 Alleviates LPS Induced Acute Lung Injury by Inhibiting STAT3 Phosphorylation and Regulating Endothelial Tight Junctions

Single-Cell Transcriptomics Reveals Crucial Cell Subsets and Functional Heterogeneity Associated With Carotid Atherosclerosis and Cerebrovascular Events

Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation

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