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PubMed2006

Cyclic phosphatidic acid stimulates respiration without producing vasopressor or tachycardiac effects in rats.

The effects of a novel lipid mediator, cyclic phosphatidic acid (cPA), on respiratory and cardiovascular functions were examined in anesthetized rats. Intravenous (i.v.) administration of 3-O-carba-oleoyl-cPA at doses of 130 and 390 microg/kg produced dose-dependent increases in tidal volume and respiratory frequency, resulting in an increase in total ventilation. Heart rate was slightly decreased at a dose of 390 microg/kg, while systemic arterial pressure was not affected. Bilateral section of vagi and carotid sinus nerves designed to eliminate major regulatory inputs from the peripheral afferents to the respiratory center reduced these responses, but did not abolish them. These results indicate that cPA stimulates respiration, via central and peripheral mechanisms acting on the central respiratory rhythm generator in the brain stem. Administration of cPA may be of therapeutic value as a respiratory stimulant without producing vasopressor or tachycardiac effects, for treatment of respiratory disorders.

Animals↗

PubMed2004

Formation of phosphatidic acid, ceramide, and diglyceride on radiolysis of lipids: identification by MALDI-TOF mass spectrometry.

By use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, phosphatidic acid was found to be the main product of gamma radiolysis of cardiolipin, phosphatidylinositol, and phosphatidylglycerol. It has been shown that gamma irradiation of such glycolipids as cerebroside and galactosyl diglyceride leads to formation of ceramide and diglyceride, respectively. These findings, combined with those obtained earlier, allowed an assumption to be made that, owing to radiation-induced free radical fragmentation of lipids in their polar moiety, formation of signaling molecules can occur.

Animals↗

PubMed2004

Phosphatidic acid and tumor necrosis factor-alpha induce the expression of CD83 through mitogen activated protein kinase pathway in a CD34+ hematopoietic progenitor cell line, KG1.

To elucidate the signaling pathways involved in the expression of CD83, which is linked to the differentiation and maturation states of dendritic cells, we examined the effect of phosphatidic acid (PA) on the expression of CD83 in KG1, a CD34(+) hematopoietic progenitor cell. In the presence of tumor necrosis factor (TNF)-alpha, PA but not lyso-PA up-regulated CD83 on KG1 cells. Moreover, PA and TNF-alpha-induced expression of CD83 was slightly increased by propranolol, an inhibitor of PA phosphohydrolase but was unaffected by phospholipase A2 inhibitor. PA and TNF-alpha increased the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2, p38-kinase, and c-Jun N-terminal kinase (JNK) by Western blotting. However, the up-regulation of CD83 by PA/TNF-alpha on KG1 was significantly abrogated by PD98059, a specific inhibitor of ERK kinase, but was enhanced by SP600125, a JNK inhibitor. Bis-indolylmaleimide, an inhibitor of protein kinase C, partially blocked the up-regulation of CD83 and ERK phosphorylation induced by PA and TNF-alpha. Moreover, the incubation of KG1 cells with phorbol ester and TNF-alpha for 5 days increased the protein level of phospholipase D. These results suggest that PA and TNF-alpha induce the up-regulation of CD83 and that their action is regulated by ERK and JNK.

Antigens, CD↗

PubMed2006

Signaling functions of phosphatidic acid.

Phosphatidic acid (PA) has emerged as a new class of lipid mediators involved in diverse cellular functions in plants, animals, and microorganisms. Considerable progress has been made recently on the production, cellular function, and mode of action of PA in the cell. The cellular levels of PA undergo dynamic changes in response to developmental and environmental stimuli. The production of signaling PA is mediated by families of multiple enzymes that regulate the timing, location, amount, and molecular species of PA. A number of PA target proteins have been identified, which include proteins involved in phosphorylation and dephosphorylation of proteins and lipids, as well as in G protein regulation, vesicular trafficking, and metabolism. PA mediates cellular functions through different modes of action, such as membrane tethering, modulation of enzymatic activities, and/or structural effects on cell membranes. The regulatory processes in which PA has been implicated include signaling pathways in cell growth, proliferation, reproduction, and responses to hormones and biotic and abiotic stresses.

Animals↗

PubMed2005

Phosphatidic acid: a multifunctional stress signaling lipid in plants.

Phosphatidic acid (PA) has only recently been identified as an important signaling molecule in both plants and animals. Nonetheless, it already promises to rival the importance of the classic second messengers Ca(2+) and cAMP. In plants, its formation is triggered in response to various biotic and abiotic stress factors, including pathogen infection, drought, salinity, wounding and cold. In general, PA signal production is fast (minutes) and transient. Recently, our understanding of the role of PA formation in stress responses as a result of phospholipases C and D activity has greatly increased. Moreover, the first protein targets of PA have been identified. Based on this recent work, potential mechanisms by which PA provokes downstream effects are emerging.

Amino Acid Sequence↗

PubMed1998

Chain-melting transition temperatures of phospholipids with acylated or alkylated headgroups (N-acyl phosphatidylethanolamines and O-alkyl phosphatidic acids), or with alpha-branched chains.

The biphasic dependence of the chain-melting transition temperature on chainlength, nN, of the headgroup-attached chain of N-acyl phosphatidylethanolamines and of O-alkyl phosphatidic acids is interpreted in terms of a different linear dependence of the transition enthalpy and entropy on nN for long and short chains, respectively. A consistent expression of the form [equation: see text], where DeltanN is the critical chainlength at which the packing mode of the headgroup-attached chains changes, is found to apply systematically to the transition temperatures for both sets of lipids, over the range nN=2-18. This thermodynamic analysis demonstrates that the headgroup-attached chain is located in an environment that differs for long and short chains. Similar considerations apply also to phosphatidylcholines with alpha-branched glycerol-attached chains.

Entropy↗

PubMed1997

Exogenous phosphatidic acid with saturated short-chain fatty acyl groups induces superoxide anion release from guinea pig peritoneal polymorphonuclear leukocytes by three different mechanisms.

Treatment of suspensions of guinea pig peritoneal polymorphonuclear leukocytes (PMN) with four species of phosphatidate (PA) containing short-chain fatty acids induced sustained superoxide anion (O2-) production after a lag time. The rank order of efficiency of these PAs in triggering O2- production was PA8:0 [1,2-dioctanoyl-sn-glycerol-3-phosphate (GP)] > PA10:0 (1,2-didecanoyl-GP) > PA6:0 (1,2-dicaproyl-GP) > > PA12:0 (1,2-dilauroyl-GP). The O2- release from PMN stimulated with PA10:0 or PA12:0, but not with PA6:0 or PA8:0, was lowered by the addition of 1 mM extracellular Ca2+. Studies with various inhibitors showed that the mechanism of multiphasic O2- production induced by PA8:0 depended on its concentration: 1 and 3 microM PA8:0 induced O2- production constantly after a lag time through a protein kinase-dependent mechanism that was inhibited by 100 nM staurosporine. With concentrations of PA of 10 microM or more, an additional mechanism that was independent of protein kinase became operative and predominant over the protein kinase-dependent one. This protein kinase-independent mechanism was inhibited selectively by 80 microM TMB-8. Concentrations of 30, 60 and 100 microM PA first elicited transient O2- production via another protein kinase-dependent mechanism that was more sensitive to H-7 than to staurosporine, and then sustained O2- production, mainly driven by the protein kinase-independent mechanism. Metabolism of exogenously added [14C]PA8:0 in intact PMN was examined in the presence and absence of propranolol. Results suggest that PA itself is more important rather than its degradation products such as diacylglycerol, in inducing O2- production via three different mechanisms described above.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1997

Tyrosine phosphorylation of 100-115 kDa proteins by phosphatidic acid generated via phospholipase D activation in HL60 granulocytes.

In HL60 granulocytes, 4beta-phorbol 12-myristate 13-acetate (PMA) induced tyrosine phosphorylation of several proteins with molecular weight of 100-115 kDa and 45 kDa. Furthermore, PMA-mediated phosphatidic acid (PA) production via phospholipase D (PLD) activation. In the presence of either butanol or ethanol, PMA-induced PA production was markedly reduced and instead a metabolically stable phosphatidylbutanol (PBut) or phosphatidylethanol (PEt) was produced by transphosphatidylation by PLD. Under the same incubation condition, these primary alcohols inhibited PMA-induced tyrosine phosphorylation of the 100-115 kDa proteins. Propranolol, which is often used as a selective inhibitor of PA phosphohydrolase (PAP) involving diacylglycerol (DG) formation from PA, did not affect tyrosine phosphorylation of the 100-115 kDa proteins. Moreover, incubation of HL60 granulocytes with Streptomyces chromofuscus PLD caused both PA production and tyrosine phosphorylation of the above proteins. Exogenous PA treatment also induced tyrosine phosphorylation of the same proteins. Thus, the results presented here suggest that PA produced via PLD activation is involved in tyrosine phosphorylation of the 100-115 kDa proteins in HL60 granulocytes.

Blotting, Western↗

PubMed1997

Phosphatidic acid phosphatase from mammalian tissues: discovery of channel-like proteins with unexpected functions.

Phosphatidic acid phosphatase (PAP) has long been known as a key enzyme involved in both glycerolipid biosynthesis and cellular signal transduction. The cDNA cloning of a plasma membrane-bound type 2 PAP has revealed the existence of a novel glycoprotein with six transmembrane domains. The type 2 PAP now represents an enzyme family consisting of Drosophila Wunen and rat Dri 42, which participate in germ cell migration and epithelial differentiation, respectively. Such novel functions of the type 2 PAP suggest the unexpected importance of lipids and/or their metabolic enzymes.

Amino Acid Sequence↗

PubMed1998

Phospholipase D and phosphatidic acid enhance the hydrolysis of phospholipids in vesicles and in cell membranes by human secreted phospholipase A2.

Phosphatidyl-choline (PC) vesicles and normal cell membranes are resistant to hydrolysis by human group II secreted PLA2, an enzyme that can attain high concentrations in extracellular fluids during many inflammatory processes. This highly cationic enzyme (pI>10.5) has a marked preference for anionic phospholipid interfaces, normally present within the cell. Therefore, the ability of one such anionic phospholipid, phosphatidic acid (PA), to enhance the activity of this enzyme has been investigated in detail. Results using model membrane vesicles and a continuous fluorescence assay highlight the ability of low molar proportions of PA to stimulate vesicle hydrolysis and this stimulation with increasing PA was parallelled by enhanced interfacial binding. In contrast, no productive binding of this enzyme could be detected to the surface of pure PC vesicles. The enhancement of hydrolysis in the presence of PA could also be achieved by prior treatment of pure PC vesicles with PLD, an effect that was dependent on the concentration of PLD and the duration of exposure to this enzyme. The fluorescence assay also allowed cell membranes and whole cells to be used as substrates and whereas such membrane presentations were refractory to hydrolysis by the human enzyme, prior treatment with PLD allowed hydrolysis using concentrations of this PLA2 that would be found extracellularly under inflammatory conditions. These results highlight the potential for PA, generated at the surface of the cell membrane, to be hydrolysed by extracellular human sPLA2 with the generation of lysophosphatidic acid and other lipid mediators and provides one possible mechanism whereby this human sPLA2 could become pro-inflammatory.

Calcium↗

PubMed2003

Depressed phosphatidic acid-induced contractile activity of failing cardiomyocytes.

The effects of phosphatidic acid (PA), a known inotropic agent, on Ca(2+) transients and contractile activity of cardiomyocytes in congestive heart failure (CHF) due to myocardial infarction were examined. In control cells, PA induced a significant increase (25%) in active cell shortening and Ca(2+) transients. The phospholipase C (PLC) inhibitor, 2-nitro-4-carboxyphenyl N,N-diphenylcarbonate, blocked the positive inotropic action induced by PA, indicating that PA induces an increase in contractile activity and Ca(2+) transients through stimulation of PLC. Conversely, in failing cardiomyocytes there was a loss of PA-induced increase in active cell shortening and Ca(2+) transients. PA did not alter resting cell length. Both diastolic and systolic [Ca(2+)] were significantly elevated in the failing cardiomyocytes. In vitro assessment of the cardiac sarcolemmal (SL) PLC activity revealed that the impaired failing cardiomyocyte response to PA was associated with a diminished stimulation of SL PLC activity by PA. Our results identify an important defect in the PA-PLC signaling pathway in failing cardiomyocytes, which may have significant implications for the depressed contractile function during CHF.

Animals↗

PubMed2003

Oxidant stress enhances Lyso-PAF-AcT activity by modifying phospholipase D and phosphatidic acid in aortic endothelial cells.

Oxidant stress, as a consequence of selenium (Se) deficiency, alters production of vasoactive compounds including platelet-activating factor (PAF). Recent studies report that enhanced PAF production during Se deficiency is a consequence of increased lyso-PAF:acetyl-coenzyme A acetyltransferase (Lyso-PAF-AcT) activity. To elucidate the mechanism behind increased Lyso-PAF-AcT activity during oxidant stress, phospholipase D (PLD) activity and phosphatidic acid (PA) production were examined. Increased PLD activity and PA production were exhibited in bovine aortic endothelial cells using a Se-deficient model of oxidant stress. The direct effects of PLD and PA on Lyso-PAF-AcT activity were assessed using selective inhibitors and repletion experiments. Following the inhibition of PLD and addition of exogenous PA, Lyso-PAF-AcT activity significantly decreased and increased, respectively. Therefore, Se deficiency enhances Lyso-PAF-AcT activity in part by modifying PLD and PA. This suggests a novel link between Se status and PAF production, providing potential upstream therapeutic targets for PAF regulation under conditions of oxidant stress.

Acetyltransferases↗

PubMed2003

Phosphatidic acid production, required for cholecystokinin octapeptide-stimulated amylase secretion from pancreatic acinar AR42J cells, is regulated by a wortmannin-sensitive process.

To investigate the role of phospholipids in exocytotic secretory events, we utilized rat pancreatic acinar AR42J cells that secreted amylase in response to cholecystokinin octapeptide (CCK-8). Wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), was found to inhibit the secretion in a dose-dependent manner. When changes in cell membrane phospholipids were investigated before and after CCK-8 stimulation using [32P]orthophosphoric acid-labeled AR42J cells, we observed a rapid increase in phosphatidic acid (PtdOH) levels right after stimulation, which was not observed in non-stimulated cells. The increase, however, was suppressed by wortmannin pre-treatment, which also inhibited amylase secretion. Changes in other major phospholipids were not significant. These results indicate that CCK-8 induces amylase secretion through PI3K-regulated production of PtdOH in cell membranes.

Amylases↗

PubMed1990

Diacylglycerol and phosphatidate production and the exocytosis of the sperm acrosome.

We have investigated the production of diacylglycerol (DAG) and phosphatidate (PtdOH) during the exocytosis of the sperm acrosome. Ram spermatozoa treated with Ca2+ and the ionophore A23187 experienced a rapid breakdown of the polyphosphoinositides (PPIs), and a rise in [32P]Pi-labelled PtdOH and DAG mass; PtdOH mass, however, was unaffected. Treatment with Ca2+/A23187 and the DAG kinase inhibitor R59022 resulted in a dose-dependent increase in DAG mass and a concomitant decrease in [32P]PtdOH; such treatment showed a dose-dependent stimulation of acrosomal exocytosis. Pre-incubation with exogenous PtdOHs before stimulation with Ca2+/A23187 did not affect the time-course of exocytosis, whereas treatment with Ca2+/A23187 and exogenous DAGs (dioctanoylglycerol, oleoyl-acetyl-glycerol, or dioleoylglycerol) resulted in a dose-dependent stimulation of acrosomal exocytosis. Our results suggest that DAG, rather than PtdOH, is the important metabolite generated upon PPI hydrolysis; however, since spermatozoa lack protein kinase C, the target of DAG in most cells, a role for DAG in acrosomal exocytosis is as yet unclear.

Acrosome↗

PubMed1988

Phorbol ester treatment inhibits thrombin but not stable GTP analogue-induced platelet granule secretion despite inhibition of phosphatidate formation with both agonists.

Previous work has demonstrated that pre-treatment of platelets with phorbol esters that activate protein kinase C eg phorbol 12-myristate 13-acetate (PMA) results in an inhibition of inositol phospholipid breakdown and granule secretion induced by physiological agonists such as thrombin and collagen. In the present study, the effect of pre-treatment with PMA on granule secretion and [32P]-phosphatidate (PA) formation induced by the stable GTP analogue, guanosine 5'-[gamma thio] triphosphate (GTP gamma S) was examined in saponin-permeabilized platelets. A low concentration of PMA ie 1.6nM, that did not induce significant 5-hydroxytryptamine (5HT) secretion on its own, but inhibited low-dose thrombin-induced 5HT secretion totally and PA formation by 30-40% in intact as well as permeabilised platelets was chosen. Our results demonstrate a lack of inhibition of GTP gamma S (40 microM)-induced 5HT secretion by PMA in permeabilised platelets, despite significant inhibition (70%) of PA formation, suggesting that apart from the diacylglycerol pathway of secretion which may be common to thrombin and GTP analogues, secretion induced by physiological agonists such as thrombin may involve another mechanism that is inhibitable by phorbol esters.

Blood Platelets↗

PubMed2003

Modification of intracellular free calcium in cultured A10 vascular smooth muscle cells by exogenous phosphatidic acid.

Exogenous phosphatidic acid (PA) was observed to produce a concentration-dependent increase in [Ca(2+)](i) in cultured A10 vascular smooth muscle cells. Preincubation of cells with sarcoplasmic reticulum Ca(2+)-ATPase inhibitors (cyclopiazonic acid and thapsigargin), a phospholipase C inhibitor (2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate), inositol 1,4,5-trisphosphate receptor antagonists (2-aminoethoxydiphenyl borate and xestospongin), and an activator of protein kinase C (PKC) (phorbol 12-myristate 13-acetate) depressed the PA-evoked increase in [Ca(2+)](i). Although EGTA, an extracellular Ca(2+) chelator, decreased the PA-induced increase in [Ca(2+)](i), sarcolemmal Ca(2+)-channel blockers (verapamil or diltiazem) did not alter the action of PA. On the other hand, inhibitors of PKC (bisindolylmaleimide I) and G(i)-protein (pertussis toxin) potentiated the increase in [Ca(2+)](i) evoked by PA significantly. These results suggest that the PA-induced increase in [Ca(2+)](i) in vascular smooth muscle cells may occur upon the activation of phospholipase C and the subsequent release of Ca(2+) from the inositol 1,4,5-trisphosphate-sensitive Ca(2+) pool in the sarcoplasmic reticulum. This action of PA may be mediated through the involvement of PKC.

Animals↗

PubMed1996

Stimulation of protein synthesis by phosphatidic acid in rat cardiomyocytes.

Phosphatidic acid (PA) was observed to stimulate protein synthesis in adult cardiomyocytes in a time- and concentration-dependent manner. The maximal stimulation in protein synthesis (142 +/- 12% vs 100% as the control) was achieved at 10 microM PA within 60 min and was inhibited by actinomycin D (107 +/- 4% of the control) or cycloheximide (105 +/- 6% of the control). The increase in protein synthesis due to PA was attenuated or abolished by preincubation of cardiomyocytes with a tyrosine kinase inhibitor, genistein (94 +/- 9% of the control), phospholipase C inhibitors 2-nitro-4-carboxyphenyl N,N-diphenyl carbamate or carbon-odithioic acid O-(octahydro-4,7-methanol-1H-inden-5-yl (101 +/- 6 and 95 +/- 5% of the control, respectively), protein kinase C inhibitors staurosporine or polymyxin B (109 +/- 3 and 93 +/- 3% of the control), and chelators of extracellular and intracellular free Ca2+ EGTA or BAPTA/AM (103 +/- 6 and 95 +/- 6% of the control, respectively). PA at different concentrations (0.1 to 100 microM) also caused phosphorylation of a cell surface protein of approximately 24 kDa. In addition, mitogen-activated protein kinase was stimulated by PA in a concentration-dependent manner; maximal stimulation (217 +/- 6% of the control) was seen at 10 microM PA. These data suggest that PA increases protein synthesis in adult rat cardiomyocytes and thus may play an important role in the development of cardiac hypertrophy.

Animals↗

PubMed1998

Inhibition by aminosalicylates of phosphatidic acid formation induced by superoxide, calcium or spermine in enterocyte mitochondria.

Inflammation is associated with oxidative stress and altered cellular calcium homeostasis. Our earlier studies have shown that, increased phosphatidic acid (PA) formation occurred in enterocyte mitochondria when exposed to superoxide, divalent metal ions or polyamines resulting in altered lipid composition. Since aminosalicylates are the drug of choice for gut inflammation, we have tested the effect of aminosalicylates on PA formation by enterocyte mitochondria. When stimulated by superoxide, Ca2+ or spermine, phosphatidyleth-anolamine (PE) degradation and PA formation occurred in enterocyte mitochondria which can be inhibited by aminosalicylates. The inhibition was 50-60% at 0.5-mM concentration and at 1- or 2-mM final concentration, complete inhibition was observed. Both 5-aminosalicylate (5-ASA) and 4-aminosalicylate (4-ASA) showed similar effects. The stimulation of PA formation by calcium or spermine was not due to increased generation of superoxide by mitochondria which was confirmed by measurement of superoxide production by the mitochondria. These studies suggest that in addition to other cellular effects, aminosalicylates may prevent the enterocyte mitochondrial damage by inhibition of PA formation and PE degradation and alteration of mitochondrial lipid composition.

Aminosalicylic Acid↗