Phospholipid scramblase 1 is required for β2-glycoprotein I binding in hypoxia and reoxygenation-induced endothelial inflammation

Abstract

Multiple pathologic conditions, including hemorrhage, tumor angiogenesis, and ischemia-reperfusion events, will result in hypoxia and subsequent reperfusion. Previous studies have analyzed the lipid changes within whole tissues and indicated that ischemia-reperfusion altered tissue and cellular phospholipids. Using an in vitro cell culture model of hypoxia and reoxygenation, we examined the endothelial lipid changes. We hypothesized that phospholipid scramblase 1, a protein that regulates bilayer asymmetry, is involved in altering the phospholipids of endothelial cells during hypoxia, a component of ischemia, leading to β2-glycoprotein I and IgM binding and subsequent lipid-mediated, inflammatory responses. We have completed the first comprehensive study of steady-state phospholipid scramblase 1 mRNA levels, protein expression, and activity under conditions of hypoxia and reoxygenation. Phospholipid scramblase 1 regulates phosphatidylserine exposure in response to oxygen stress, leading to β2-glycoprotein I and IgM binding and lipid-mediated, inflammatory responses.

Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia

“…Similarly, GLO1 confers a stress-inducible enzymatic defense against dicarbonyl stress associated with aging and was found associated with multidrug-resistant tumors (70). As PLSCR1 mediates inflammation-induced phosphatidylserine exposure and subsequent apoptosis induction (38), the observed down-regulation ( Fig. 2D) may again relate to chronic inflammation and reduced cell death.…”

“…Loss of function of the cellular energy homoeostasis protein AMPD2 was found associated with neurodegeneration (36), whereas down-regulation of the sodium-dependent serotonin transporter SLC6A4 was described as marker of life adversity exposure clearly associated with massive stress (37). The down-regulation of PLSCR1 may most plausibly inhibit inflammatory responses resulting from acute cell stress as described in case of hypoxia and reoxygenation (38). TBXAS1 has been described to be expressed at significantly reduced levels in high-grade breast tumors and tumor patients with poor prognosis (39).…”

<p>Extracellular vesicles released by J774A.1 macrophages reduce the bacterial load in macrophages and in an experimental mouse model of tuberculosis</p>

“…Mtb-EV had an increased content of phosphatidylserine, as assessed by thin-layer chromatography (a method with higher sensitivity than flow cytometry). This increase in phosphatidylserine content could be caused by the activity of phospholipid scramblase 1(PLSCR1), since this enzyme transports phosphatidylserine from the inner to the outer layer of cellular membranes39 and is overexpressed in patients with tuberculosis 40…”

Attenuation of endothelial phosphatidylserine exposure decreases ischemia-reperfusion induced changes in microvascular permeability

“…Phosphatidylserine exposure during hypoxia-reoxygenation is associated with microvascular dysfunction. In vitro , hypoxia (2h) and reoxygenation (1h) in murine endothelial cells is associated with increased extracellular beta-2 glycoprotein binding to endothelium (beta-2 glycoprotein has high affinity for anionic phospholipids such as PS) as demonstrated by increased Annexin-V immunofluorescence [16]. In that study, PLSCR1 mRNA was upregulated in hypoxia-treated cells, and hypoxia with subsequent reoxygenation increased protein expression of PLSCR1.…”

“…In endothelial cells, PS exposure occurs during the systemic capillary leak syndrome [14] and (LPS)-induced myocardial damage in cardiac endothelium [15]. In models of hypoxia-reoxygenation, PS exposure is linked to IgM binding and promulgation of the inflammatory response [16]. In intestinal ischemia-reperfusion injury, PS exposure promotes intestinal hyperpermeability [17].…”