Roles for lysophosphatidic acid signaling in vascular development and disease

Smyth, Susan S.; Kræmer, Maria; Yang, Liping; Hoose, Patrick Van; Morris, Andrew J.

doi:10.1016/j.bbalip.2020.158734

Cited by 22 publications

(20 citation statements)

References 52 publications

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“…The tissue coagulation factor III directly exposed to the blood in the arterial smooth muscle activates the exogenous coagulation pathway and promotes the coagulation cascade ( 13 ). Platelets, an indispensable role in the coagulation cascade, are continuously activated by the LPC-ATX-LPA pathway to produce more LPA before the aortic dissection is surgically repaired ( 14 , 36 ). Although some studies speculate that the half-life of LPA is only 2–3 min under the action of LPPs, the continuous existence of disruption to the aortic media and positive feedback may be a reasonable explanation for the increase in plasma LPA in AAD patients ( 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid May Be a Novel Biomarker for Early Acute Aortic Dissection

et al. 2022

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Background: Misdiagnosis and delayed diagnosis of acute aortic dissection (AAD) significantly increase mortality. Lysophosphatidic acid (LPA) is a biomarker related to coagulation cascade and cardiovascular-injury. The extent of LPA elevation in AAD and whether it can discriminate sudden-onset of acute chest pain are currently unclear.Methods: We measured the plasma concentration of LPA in a cohort of 174 patients with suspected AAD chest pain and 30 healthy participants. Measures to discriminate AAD from other acute-onset thoracalgia were compared and calculated.Results: LPA was significantly higher in AAD than in the AMI, PE, and the healthy (344.69 ± 59.99 vs. 286.79 ± 43.01 vs. 286.61 ± 43.32 vs. 96.08 ± 11.93, P < 0.01) within 48 h of symptom onset. LPA level peaked at 12 h after symptom onset, then gradually decreased from 12 to 48 h in AAD. LPA had an AUC of 0.85 (0.80–0.90), diagnosis threshold of 298.98 mg/dl, a sensitivity of 0.81, specificity of 0.77, and the negative predictive value of 0.85. The ROC curve of LPA is better than D-dimer (P = 0.041, Delong test). The decision curve showed that LPA had excellent standardized net benefits.Conclusion: LPA showed superior overall diagnostic performance to D-dimer in early AAD diagnosis may be a potential biomarker, but additional studies are needed to determine the rapid and cost-effective diagnostic tests in the emergency department.

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid May Be a Novel Biomarker for Early Acute Aortic Dissection

et al. 2022

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“…As ATX is largely responsible for extracellular LPA synthesis, it would be complementary to quantify LPA levels in the same samples of this study. However, the analyzed serum samples cannot be used because blot clotting and platelet activation stimulate massive LPA release [ 49 ]. Moreover, all samples should have been collected in siliconized tubes, to avoid the known attachment of lipids to tubing, and kept at –80 °C or lower without repeated freeze thawing [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells

Nikitopoulou

Fanidis

Ntatsoulis

et al. 2021

IJMS

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Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.

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“…Not only are the BCSCs enriched in arteriolar niche, intriguingly, this study also shows that the BCSCs that are positive for both PKD-1 and CD36 come out of tumor nests and appear within the vascular niche, particularly arteriolar niche. Additionally, PKD-1 signaling may promote metastatic potential of BCSCs via upregulation of CD36 in BCs (46), and LPA signaling was also proposed as a therapeutic target for vascular inflammation, atherosclerosis, and potentially calcific aortic valve disease (109). Our current study indicates that inhibition of the LPA/PKD-1 pathway may likely disrupt the arteriolar niche for CSCs and eradicate BCSCs as a double-edge sword, thereby alleviating therapeutic resistance and controlling relapse and metastasis of cancers.…”

Section: Discussionmentioning

confidence: 69%

LPA/PKD-1 signaling promotes development of arteriolar niche that supports self-renewal of breast cancer stem cells and stemness

Jiang

Guo

Hao

et al. 2020

Preprint

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Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. However, the regulatory mechanisms of self-renewal and interactions with the vascular niche within tumor microenvironment are currently under investigation. Here, we demonstrate that BCSCs are enriched within arteriolar niche within the tumor microenvironment of estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the LPA/PKD-1 signaling pathway, which promotes arteriolar differentiation and self-renewal. Furthermore, this pathway directly promotes stemness features. These findings suggest that targeting LPA/PKD-1 signaling may disrupt the arteriolar niche within the tumor microenvironment and concomitantly eradicate BCSCs, thereby attenuating BC progression.

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Roles for lysophosphatidic acid signaling in vascular development and disease

Cited by 22 publications

References 52 publications

Lysophosphatidic Acid May Be a Novel Biomarker for Early Acute Aortic Dissection

Lysophosphatidic Acid May Be a Novel Biomarker for Early Acute Aortic Dissection

Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells

LPA/PKD-1 signaling promotes development of arteriolar niche that supports self-renewal of breast cancer stem cells and stemness

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