Glycosylphosphatidylinositol-Specific Phospholipase D Is Expressed by Macrophages in Human Atherosclerosis and Colocalizes With Oxidation Epitopes

O’Brien, Kevin D.; Pineda, Christine; Chiu, Winnie; Bowen, Rosario F.; Deeg, Mark A.

doi:10.1161/01.cir.99.22.2876

Cited by 52 publications

(29 citation statements)

References 36 publications

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“…It has been suggested that this treatment may relax conformational constraints on the active site of the enzyme which exists when it is anchored in the lipid bilayer, thus resulting in increased affinity for the substrate (52). Similar to other GPI-anchored proteins (53), membrane-bound Hyal2 is susceptible to specific GPIphospholipase D (GPI-PLD) (54), induced in inflammatory and oxidative stress conditions (55,56); thus it is tempting to speculate that membrane bound and soluble forms may perform different biological functions. For instance, GPI-anchored Hyal2 is likely involved in normal HA turnover, where Hyal2 depolymerize HA into ϳ20 kDa (ϳ50 disaccharides units) fragments, delivering them for further lysosomal degradation by Hyal1 (39,50).…”

Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation

Monzón

Fregien

Schmid

et al. 2010

Journal of Biological Chemistry

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Hyaluronidase 2 (Hyal2) is a hyaluronan (HA)-degrading enzyme found intracellularly or/and anchored to the plasma membrane through glycosylphosphatidylinositol (GPI). Normal human bronchial epithelial cells (NHBE) grown at the air-liquid interphase (ALI), treated with PI-specific phospholipase C (PI-PLC), exhibited increased Hyal activity in secretions and decreased protein and activity on the apical membrane, confirming that GPI-anchored Hyal2 is expressed in NHBE cells and it remains active in its soluble form. We have reported that HA degradation was mediated by reactive oxygen species (ROS) in human airways. Here we show that ROS increase Hyal2 expression and activity in NHBE cells and that the p38MAPK signaling pathway is involved in this effect. Hyal2 induction was confirmed by using small interfering RNA (siRNA) expressing lentivirus. These in vitro findings correlated in vivo with smokers, where increased Hyal2 immunoreactivity in the epithelium was associated with augmented levels of HA and the appearance of low molecular mass HA species in bronchial secretions. In summary, this work provides evidence that ROS induce Hyal2, suggesting that Hyal2 is likely responsible for the sustained HA fragmentation in the airway lumen observed in inflammatory conditions associated with oxidative stress. Hyaluronan (HA)3 is a non-sulfated glycosaminoglycan found in the extracellular matrix, in body fluids, and in secretions of mammals. HA is synthesized by three transmembrane isoenzymes: HAS1, HAS2, and HAS3 at the inner face of the plasma membrane and translocated into the extracellular space (1).The association with various binding proteins (2, 3) confers HA with a unique plasticity to organize extracellular matrix (ECM) in a tissue specific fashion (for review see Ref. 4), varying from a tightly cross-linked mesh in cartilage to a highly hydrated matrix in dermis and vitreous humor (5).In addition, HA induces intracellular signaling by binding specific receptors at the cell surface, (6, 7) orchestrating a variety of host responses generally requiring an extensive deposition of a HA in the ECM. This deposition is essential for cumulus oophorus fertilization (8) as well as for proliferation and migration of mesenchymal cells. Airway smooth muscle cells exposed to polyinosinic acid-polycytidylic acid synthesize an abnormal HA matrix with cable-like structures that bind and retains leukocytes (9, 10), suggesting that HA play key roles on host defense against infections as well.Biological functions of HA are associated with its size (6, 11). For instance, high molecular weight HA (HMWHA) exhibit anti-angiogenic, anti-inflammatory, and immunosuppressive effects while small HA fragments are angiogenic and proinflammatory (12, 13). The contrasting responses elicited by different sizes of HA are exemplified in a recent report in which HMWHA attenuated while low molecular weight HA (LMWHA) increased ozone-induced airway hyperreactivity, in a mouse model of asthma (14).In human airway epithelium, HA is present at the lumen as...

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Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation

Monzón

Fregien

Schmid

et al. 2010

Journal of Biological Chemistry

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“…Several experimental studies support the concept that PLD activation is a key event in various fundamental processes of coronary plaque destabilization: stimulation of macrophages by oxidized LDL (64 ), secretion of MMPs (65 ), activation of platelets by collagen and thrombin (66,67 ), and promotion of fibrinogen binding to the glycoprotein IIb/IIIa receptor (68 ). Isoenzymes of PLD are produced by macrophages in human coronary plaques and colocalize with oxidation epitopes (69 ). Furthermore, early ischemic membrane damage and phospholipid breakdown by phospholipases (70 ) lead to release of choline into plasma followed by a secondary uptake into blood cells by a choline transport system (71 ).…”

Section: Cholinementioning

confidence: 99%

Future Biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome

et al. 2005

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Background: Evaluation of patients who present to the hospital with a complaint of chest pain or other signs or symptoms suggestive of acute coronary syndrome (ACS) is time-consuming, expensive, and problematic. Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cardiac troponins I and T), such as inflammatory cytokines, cellular adhesion molecules, acute-phase reactants, plaque destabilization and rupture biomarkers, biomarkers of ischemia, and biomarkers of myocardial stretch may provide earlier assessment of overall patient risk and aid in identifying patients with higher risk of an adverse event.

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“…Another potential mechanism responsible for the activation of PLD in the monocyte-macrophage system is the involvement of PLD in the secretion of matrix metallo proteinases [27], which are crucial for causing plaque rupture. Furthermore, a change of PLD expression has been demonstrated in human plaque macrophages being colocalized with oxidation epitopes [28]. PA has been shown to promote fibrinogen binding to the glycoprotein (GP) IIb/ IIIa receptor [29], which is of fundamental importance for the pathophysiology of ACS.…”

Section: Discovery Of Choline As a Marker In Acute Coronary Syndromementioning

confidence: 99%

Choline in acute coronary syndrome: an emerging biomarker with implications for the integrated assessment of plaque vulnerability

Danne

Möckel

2010

Expert Review of Molecular Diagnostics

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Glycosylphosphatidylinositol-Specific Phospholipase D Is Expressed by Macrophages in Human Atherosclerosis and Colocalizes With Oxidation Epitopes

Abstract: Collectively, these results suggest that oxidative processes may regulate GPI-PLD expression and suggest a role for GPI-PLD in inflammation and in the pathogenesis of atherosclerosis.

Cited by 52 publications

References 36 publications

Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation

Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation

Future Biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome

Choline in acute coronary syndrome: an emerging biomarker with implications for the integrated assessment of plaque vulnerability

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