A Phosphatidic Acid-activated Protein Kinase and Conventional Protein Kinase C Isoforms Phosphorylate p22 , an NADPH Oxidase Component

Regier, Debra S.; Waite, Kristin; Wallin, Reidar; McPhail, Linda C.

doi:10.1074/jbc.274.51.36601

Cited by 73 publications

(62 citation statements)

References 79 publications

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“…In the current study, PKCβ2 production and p22 phox expression were increased in diabetic Ntg hearts but not diabetic caPI3K hearts. PKCβ2 can phosphorylate p22 phox [41], and we previously demonstrated that the caPI3K transgene can blunt cardiac pathology and PKCβ2 protein production in PKCβ2-Tg mice [42]. Superoxide generation, Ask1 expression and apoptosis were elevated in hearts of diabetic Ntg and dnPI3K-Tg mice, but not in diabetic caPI3K-Tg mice.…”

Section: Discussionmentioning

confidence: 83%

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

et al. 2012

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Aims/hypothesis Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.Methods Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominantnegative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed. Results Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 phox and apoptosis signalregulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22 phox expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function. Conclusions/interpretation These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.

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Section: Discussionmentioning

confidence: 83%

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

et al. 2012

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“…We showed (24) that activation in this system is dependent on both protein kinase activity and other undefined phosphorylation-independent mechanisms. The protein kinase-dependent mechanism may involve the phosphorylation of NADPH oxidase components p47 phox and p22 phox by a novel PA-activated protein kinase (10,25,26). Alternatively, Erickson et al (17) postulated that the phosphorylation-dependent mechanism involved the conversion of DG to PA by DG kinase.…”

mentioning

confidence: 99%

Phosphatidic Acid and Diacylglycerol Directly Activate NADPH Oxidase by Interacting with Enzyme Components

Palicz

Foubert

Jesaitis

et al. 2001

Journal of Biological Chemistry

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112

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The enzyme NADPH oxidase is regulated by phospholipase D in intact neutrophils and is activated by phosphatidic acid (PA) plus diacylglycerol (DG) in cell-free systems. We showed previously that cell-free NADPH oxidase activation by these lipids involves both protein kinase-dependent and -independent pathways. Here we demonstrate that only the protein kinase-independent pathway is operative in a cell-free system of purified and recombinant NADPH oxidase components. Activation by PA ؉ DG was ATP-independent and unaffected by the protein kinase inhibitor staurosporine, indicating the lack of protein kinase involvement. Both PA and DG were required for optimal activation to occur. The drug R59949 reduced activation of NADPH oxidase by either arachidonic acid or PA ؉ DG, with IC 50 values of 46 and 25 M, respectively. The optimal concentration of arachidonic acid or PA ؉ DG for oxidase activation was shifted to the right with R59949, indicating interference of the drug with the interaction of lipid activators and enzyme components. R59949 inhibited the lipid-induced aggregation/sedimentation of oxidase components p47 phox and p67 phox , suggesting a disruption of the lipidmediated assembly process. The direct effects of R59949 on NADPH oxidase activation complicate its use as a "specific" inhibitor of DG kinase. We conclude that the protein kinase-independent pathway of NADPH oxidase activation by PA and DG involves direct interaction with NADPH oxidase components. Thus, NADPH oxidase proteins are functional targets for these lipid messengers in the neutrophil.The NADPH oxidase (the respiratory burst enzyme) in phagocytic cells produces superoxide (O 2 . ) 1 by catalyzing electron transfer from NADPH to molecular oxygen upon cell stimulation (1-3). This enzyme plays important roles in host defense against infection and in tissue damage due to inflammation (1-5). In addition, NADPH oxidase-like enzymes are present in a variety of other cell types, where the oxygen radicals formed may have signaling roles (5, 6). The enzyme in phagocytes consists of the membrane-bound heterodimeric flavocytochrome b 558 (gp91 phox and p22 phox ) and four cytosolic proteins (p47 phox , p67 phox , p40 phox , Rac1/2) (2-4, 7). Components must assemble in the membrane for the enzyme to become active (2-4, 7). The activation of NADPH oxidase is initiated by receptor-ligand interaction and involves complex intracellular signaling events. These include the activation of protein kinases to phosphorylate cellular proteins and NADPH oxidase components (2, 8) and the generation of various lipid second messengers (AA by phospholipase A 2 (9); DG by phospholipase C or PA phosphohydrolase; PA by phospholipase D or DG kinase (10, 11)). In cell-free systems, these lipids can induce activation of the enzyme (12-17). AA exerts its effect by directly acting on enzyme components (18 -22). PA has been shown to partially activate purified flavocytochrome b 558 (23), suggesting it interacts with this protein. It is not known whether DG has any direct effe...

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“…Therefore, PA is likely to be involved in numerous physiological processes in plants, including stomatal movement (Jacob et al, 1999), leaf senescence (Fan et al, 1997), various stress responses, and hormone signaling (for review, see Munnik, 2001). In vivo roles of PA in leaf senescence and stomatal closing movement were demonstrated using PLD␣ antisense plants; this mutant plant is delayed in ABA-and ethylene-induced senescence (Ryu and Wang, 1995; Fan et al, 1997;Zien et al, 2001) and in ABA-induced stomatal closing movement (Sang et al, 2001b).A potential mechanism of PA action in plant stress responses is the activation of an NADPH oxidase that produces ROS, similar to the system in neutrophils (Regier et al, 1999; Palicz et al, 2001). A recent report shows that PA promotes ROS formation in Arabidopsis (Sang et al, 2001a).…”

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confidence: 99%

“…A potential mechanism of PA action in plant stress responses is the activation of an NADPH oxidase that produces ROS, similar to the system in neutrophils (Regier et al, 1999; Palicz et al, 2001). A recent report shows that PA promotes ROS formation in Arabidopsis (Sang et al, 2001a).…”

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confidence: 99%

Phosphatidic Acid Induces Leaf Cell Death in Arabidopsis by Activating the Rho-Related Small G Protein GTPase-Mediated Pathway of Reactive Oxygen Species Generation

Gu²,

et al. 2004

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Phosphatidic acid (PA) level increases during various stress conditions. However, the physiological roles of this lipid in stress response remain largely unknown. In this study, we report that PA induced leaf cell death and elevated the levels of reactive oxygen species (ROS) in the whole leaf and single cells. To further elucidate the mechanism of PA-induced cell death, we then examined whether Rho-related small G protein (ROP) 2, which enhanced ROS production in an in vitro assay, is involved in PA-induced ROS production and cell death. In response to PA, transgenic leaves of Arabidopsis expressing a constitutively active rop2 mutant exhibited earlier cell death and higher levels of ROS than wild type (WT), whereas those expressing a dominant-negative rop2 mutant exhibited later cell death and lower ROS. However, in the absence of exogenous PA, no spontaneous cell death or elevated ROS was observed in constitutively active rop2 plants, suggesting that the activation of ROP GTPase alone is insufficient to activate the ROP-mediated ROS generation pathway. These results suggest that PA modulates an additional factor required for the active ROP-mediated ROS generation pathway. Therefore, PA may be an important regulator of ROP-regulated ROS generation and the cell death process during various stress and defense responses of plants.Phosphatidic acid (PA) is implicated in numerous stress responses of plants. Intracellular PA levels increase under various biotic and abiotic stress conditions, including pathogen elicitation (Young et al., 1996;van der Luit et al., 2000), wounding Wang, 1996, 1998; Lee et al., 1997), freezing (Welti et al., 2002), hyperosmotic stress (Munnik et al., 2000), and water deficit (Frank et al., 2000;Munnik et al., 2000). It is suggested that PA is a second messenger in a broad range of stress-signaling pathways in plants and mediates important responses to stresses (Munnik, 2001).PA has many regulatory functions in animal cells, including the regulation of reactive oxygen species (ROS) generation, protein kinase, phosphatase, lipid kinase, phospholipases, intracellular Ca 2ϩ levels, vesicle trafficking, cell proliferation, and cytoskeletal rearrangement (Liscovitch et al., 2000). This lipid also regulates a wide range of important cellular processes in plants, including regulation of ROS generation (Sang et al., 2001a), MAPK activity (Lee et al., 2001), K ϩ channels (Jacob et al., 1999), and actin organization (Lee et al., 2003). Therefore, PA is likely to be involved in numerous physiological processes in plants, including stomatal movement (Jacob et al., 1999), leaf senescence (Fan et al., 1997), various stress responses, and hormone signaling (for review, see Munnik, 2001). In vivo roles of PA in leaf senescence and stomatal closing movement were demonstrated using PLD␣ antisense plants; this mutant plant is delayed in ABA-and ethylene-induced senescence (Ryu and Wang, 1995; Fan et al., 1997;Zien et al., 2001) and in ABA-induced stomatal closing movement (Sang et al., 2001b).A potentia...

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A Phosphatidic Acid-activated Protein Kinase and Conventional Protein Kinase C Isoforms Phosphorylate p22 , an NADPH Oxidase Component

Cited by 73 publications

References 79 publications

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

Phosphatidic Acid and Diacylglycerol Directly Activate NADPH Oxidase by Interacting with Enzyme Components

Phosphatidic Acid Induces Leaf Cell Death in Arabidopsis by Activating the Rho-Related Small G Protein GTPase-Mediated Pathway of Reactive Oxygen Species Generation

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