Group VIB Calcium-Independent Phospholipase A2 (iPLA2γ) Regulates Platelet Activation, Hemostasis and Thrombosis in Mice

Yoda, Emiko; Rai, Kohmi; Ogawa, Motoyuki; Takakura, Yuki; Kuwata, Hiroshi; Suzuki, Hidenori; Nakatani, Yoshihito; Murakami, Makoto; Hara, Shuntaro

doi:10.1371/journal.pone.0109409

Cited by 20 publications

(14 citation statements)

References 32 publications

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“…Consistent with a protective role of iPLA 2 ␥ in this process, the survival rates were lowered and tissue parasitism amplifi ed in T. cruziinfected iPLA 2 ␥ -null mice, suggesting that iPLA 2 ␥ activity affords protection against acute state cardiomyopathy in Chagas' disease ( 83 ). In contrast, iPLA 2 ␥ -defi ciency has been shown to increase bleeding time and provide resistance to thromboembolism ( 84 ), raising the possibility of targeting iPLA 2 ␥ for antithrombotic drug development. To date, the only reported clinical manifestation relating to iPLA 2 ␥ is a report that its absence is associated with myocardial dysfunction, cognitive defects, and mitochondrial degeneration ( 85 ) in a case study that closely parallels the phenotype in iPLA 2 ␥ -null mice ( 73 ).…”

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confidence: 75%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

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The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

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confidence: 75%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

View full text Add to dashboard Cite

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“…iPLA 2 γ also participates in the generation of lipid mediators under certain conditions. Pnpla8 −/− mice display reduced ADP- or collagen-stimulated TXA 2 generation by platelets ex vivo and show prolonged bleeding time and reduced pulmonary thromboembolism in vivo [ 132 ]. Cardiomyocyte-specific deletion of iPLA 2 γ decreases infarct size upon ischemia/reperfusion, with reduction of oxygenated metabolites of ω3 and ω6 PUFAs including PGs, HETEs, and hydroxy-DHAs [ 133 ].…”

Section: The Ipla 2 /Pnpla Familymentioning

confidence: 99%

Updating Phospholipase A2 Biology

2020

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The phospholipase A2 (PLA2) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA2 has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA2 reaction. PLA2 enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA2-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA2 superfamily, focusing particularly on the novel roles of PLA2s in vivo.

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“…The unique properties of plasmalogens influence membrane structure and molecular dynamics, modulate the function of integral membrane proteins, and contribute to the phospholipase-mediated release of signaling fatty acids during cellular stimulation (5)(6)(7)(8)(9). Deficiencies in plasmalogen content have identified important roles for these specialized phospholipids in modulating signal transduction (10), cell proliferation (11), cholesterol trafficking (12), and sensitivity to oxidative stress (13,14). Moreover, human genetic mutations leading to deficiencies in plasmalogen biosynthesis (e.g.…”

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Cytochrome c is an oxidative stress–activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage

Jenkins

Yang

Liu

et al. 2018

Journal of Biological Chemistry

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Plasmalogens are phospholipids critical for cell function and signaling that contain a vinyl ether linkage at the -1 position and are highly enriched in arachidonic acid (AA) at the-2 position. However, the enzyme(s) responsible for the cleavage of the vinyl ether linkage in plasmalogens has remained elusive. Herein, we report that cytochrome , in the presence of either cardiolipin (CL), O and HO, or oxidized CL and O, catalyzes the oxidation of the plasmalogen vinyl ether linkage, promoting its hydrolytic cleavage and resultant production of 2-AA-lysolipids and highly reactive α-hydroxy fatty aldehydes. Using stable isotope labeling in synergy with strategic chemical derivatizations and high-mass-accuracy MS, we deduced the chemical mechanism underlying this long sought-after reaction. Specifically, labeling with either O or HO, but not with HO, resulted in M + 2 isotopologues of the α-hydroxyaldehyde, whereas reactions with both O and HO identified the M + 4 isotopologue. Furthermore, incorporation of O fromO was predominantly located at the α-carbon. In contrast, reactions with HO yielded O linked to the aldehyde carbon. Importantly, no significant labeling of 2-AA-lysolipids withO, HO, or HO was present. Intriguingly, phosphatidylinositol phosphates (PIP and PIP) effectively substituted for cardiolipin. Moreover, cytochrome released from myocardial mitochondria subjected to oxidative stress cleaved plasmenylcholine in membrane bilayers, and this was blocked with a specific mAb against cytochrome Collectively, these results identify the first plasmalogenase in biology, reveal the production of previously unanticipated signaling lipids by cytochrome, and present new perspectives on cellular signaling during oxidative stress.

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Group VIB Calcium-Independent Phospholipase A2 (iPLA2γ) Regulates Platelet Activation, Hemostasis and Thrombosis in Mice

Cited by 20 publications

References 32 publications

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Updating Phospholipase A2 Biology

Cytochrome c is an oxidative stress–activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage

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