Letter by Sonkar et al Regarding Article, “Class III PI3K Positively Regulates Platelet Activation and Thrombosis via PI(3)P-Directed Function of NADPH Oxidase”

Letter by Sonkar et al Regarding Article, “Class III PI3K Positively Regulates Platelet... Letter to the Editor Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment. Letter by Sonkar et al Regarding Article, Sources of Funding This study was supported in part by National Institutes of Health “Class III PI3K Positively Regulates Platelet grants AG049784 to S. Dayal. Activation and Thrombosis via PI(3)P-Directed Function of NADPH Oxidase” Disclosures To the Editor: None. We read with great interest the recent article by Liu et al on the role of phosphoinositide 3-kinase (PI3K) in platelet activation and Vijay K. Sonkar Steven R. Lentz thrombosis. Liu et al demonstrated that mice lacking platelet-specific Sanjana Dayal special-propertyTH VPS34, a PI3K isoform, exhibit diminished platelet activation and Department of Internal Medicine aggregation and are protected from accelerated thrombosis. This University of Iowa Carver College of Medicine phenotype was associated with loss of translocation of the p40phox Iowa City cytoplasmic subunit of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to the plasma membrane, suggesting that VPS34 References may regulate platelet reactive oxygen species (ROS) generation and 1. Liu Y, Hu M, Luo D, Yue M, Wang S, Chen X, Zhou Y, Wang Y, Cai Y, subsequent platelet activation by mediating assembly of a func- Hu X, Ke Y, Yang Z, Hu H. Class III PI3K positively regulates platelet tional NADPH oxidase. The authors did not directly measure plate- activation and thrombosis via PI(3)P-directed function of NADPH oxi- dase. Arterioscler Thromb Vasc Biol. 2017;37:2075–2086. doi: 10.1161/ let NADPH oxidase activity, however, which raises the possibility ATVBAHA.117.309751. that VPS34 may influence platelet ROS generation and aggregation 2. Dharmarajah J, Arthur JF, Sobey CG, Drummond GR. The anti-platelet through a NADPH oxidase-independent pathway. effects of apocynin in mice are not mediated by inhibition of NADPH The role of NADPH oxidase in ROS-dependent platelet acti- oxidase activity. Naunyn Schmiedebergs Arch Pharmacol. 2010;382:377– 2–4 vation and aggregation is controversial. Platelets are known to 384. doi: 10.1007/s00210-010-0552-3. 1–8 3. Walsh TG, Berndt MC, Carrim N, Cowman J, Kenny D, Metharom P. The express NADPH oxidases, which assemble from cytoplasmic role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus subunits (p47phox, p67phox, p40phox, and Rac1/2) and membrane formation. Redox Biol. 2014;2:178–186. doi: 10.1016/j.redox.2013.12.023. subunits (Nox2 and p22phox). Several studies have demonstrated 4. Delaney MK, Kim K, Estevez B, Xu Z, Stojanovic-Terpo A, Shen B, that apocynin, a nonspecific inhibitor of NADPH oxidase subunit Ushio-Fukai M, Cho J, Du X. Differential roles of the NADPH-oxidase 1 6,10 and 2 in platelet activation and thrombosis. Arterioscler Thromb Vasc Biol. assembly, prevents platelet ROS generation and aggregation, 4 2016;36:846–854. doi: 10.1161/ATVBAHA.116.307308. and Delaney et al recently reported that deficiency of Nox2 within 5. Seno T, Inoue N, Gao D, Okuda M, Sumi Y, Matsui K, Yamada S, Hirata platelets leads to decreased superoxide generation and aggregation. KI, Kawashima S, Tawa R, Imajoh-Ohmi S, Sakurai H, Yokoyama M. However, other studies have questioned the importance of NADPH Involvement of NADH/NADPH oxidase in human platelet ROS produc- tion. Thromb Res. 2001;103:399–409. oxidase in platelet ROS production, activation, and aggregation. For 2 6. Chlopicki S, Olszanecki R, Janiszewski M, Laurindo FR, Panz example, Dharmarajah et al observed that platelets isolated from T, Miedzobrodzki J. Functional role of NADPH oxidase in acti- mice lacking NADPH oxidase subunits such as Nox2 or p47Phox vation of platelets. Antioxid Redox Signal. 2004;6:691–698. doi: exhibited aggregation responses to thrombin and collagen that were 10.1089/1523086041361640. similar to platelets from wild-type mice. Additionally, they showed 7. Dayal S, Wilson KM, Motto DG, Miller FJ Jr, Chauhan AK, Lentz SR. Hydrogen peroxide promotes aging-related platelet hyperactiva- that apocynin-inhibited platelet aggregation to a similar extent in tion and thrombosis. Circulation. 2013;127:1308–1316. doi: 10.1161/ platelets from wild-type and NADPH oxidase–deficient mice. CIRCULATIONAHA.112.000966. Similar results were obtained by Walsh et al, who found that plate- 8. McCarty OJ, Larson MK, Auger JM, Kalia N, Atkinson BT, Pearce AC, lets from Nox2-deficient mice were not impaired in platelet ROS Ruf S, Henderson RB, Tybulewicz VL, Machesky LM, Watson SP. Rac1 is essential for platelet lamellipodia formation and aggregate stability under generation, activation, or aggregation responses. The explanation flow. J Biol Chem. 2005;280:39474–39484. doi: 10.1074/jbc.M504672200. for these discrepant findings in murine models is not yet under - 9. Lassègue B, Griendling KK. NADPH oxidases: functions and pathologies stood, but it is noteworthy that platelets from human patients with in the vasculature. Arterioscler Thromb Vasc Biol. 2010;30:653–661. doi: chronic granulomatous disease (a genetic disorder characterized by 10.1161/ATVBAHA.108.181610. 11,12 deficiency of Nox2) also exhibit normal aggregation responses. 10. Begonja AJ, Gambaryan S, Geiger J, Aktas B, Pozgajova M, Nieswandt B, Walter U. Platelet NAD(P)H-oxidase-generated ROS production regulates In light of these observations, it is possible that loss of VPS34 af- alphaIIbbeta3-integrin activation independent of the NO/cGMP pathway. fects platelet ROS generation and aggregation responses through Blood. 2005;106:2757–2760. doi: 10.1182/blood-2005-03-1047. pathways that are independent from NADPH oxidase assembly. 11. Pignatelli P, Carnevale R, Di Santo S, Bartimoccia S, Sanguigni V, As noted by Liu et al, both VPS34 and NADPH oxidases may Lenti L, Finocchi A, Mendolicchio L, Soresina AR, Plebani A, Violi F. represent attractive targets for antithrombotic therapeutics. Therefore, Inherited human gp91phox deficiency is associated with impaired isopros- tane formation and platelet dysfunction. Arterioscler Thromb Vasc Biol. it will be important in future studies to define the specific downstream 2011;31:423–434. doi: 10.1161/ATVBAHA.110.217885. pathways of VPS34 signaling leading to platelet activation, perhaps by 12. Pignatelli P, Sanguigni V, Lenti L, Ferro D, Finocchi A, Rossi P, Violi using genetic or pharmacological approaches to inhibit VPS34 in plate- F. gp91phox-dependent expression of platelet CD40 ligand. Circulation. lets from mice deficient in Nox2 and other NADPH oxidase subunits. 2004;110:1326–1329. doi: 10.1161/01.CIR.0000134963.77201.55. (Arterioscler Thromb Vasc Biol. 2018;38:e25. DOI: 10.1161/ATVBAHA.117.310686.) © 2018 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.117.310686 e25 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arteriosclerosis, Thrombosis, and Vascular Biology Wolters Kluwer Health

Letter by Sonkar et al Regarding Article, “Class III PI3K Positively Regulates Platelet Activation and Thrombosis via PI(3)P-Directed Function of NADPH Oxidase”

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Abstract

Letter to the Editor Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment. Letter by Sonkar et al Regarding Article, Sources of Funding This study was supported in part by National Institutes of Health “Class III PI3K Positively Regulates Platelet grants AG049784 to S. Dayal. Activation and Thrombosis via PI(3)P-Directed Function of NADPH Oxidase” Disclosures To the Editor: None. We read with great interest the recent article by Liu et al on the role of phosphoinositide 3-kinase (PI3K) in platelet activation and Vijay K. Sonkar Steven R. Lentz thrombosis. Liu et al demonstrated that mice lacking platelet-specific Sanjana Dayal special-propertyTH VPS34, a PI3K isoform, exhibit diminished platelet activation and Department of Internal Medicine aggregation and are protected from accelerated thrombosis. This University of Iowa Carver College of Medicine phenotype was associated with loss of translocation of the p40phox Iowa City cytoplasmic subunit of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to the plasma membrane, suggesting that VPS34 References may regulate platelet reactive oxygen species (ROS) generation and 1. Liu Y, Hu M, Luo D, Yue M, Wang S, Chen X, Zhou Y, Wang Y, Cai Y, subsequent platelet activation by mediating assembly of a func- Hu X, Ke Y, Yang Z, Hu H. Class III PI3K positively regulates platelet tional NADPH oxidase. The authors did not directly measure plate- activation and thrombosis via PI(3)P-directed function of NADPH oxi- dase. Arterioscler Thromb Vasc Biol. 2017;37:2075–2086. doi: 10.1161/ let NADPH oxidase activity, however, which raises the possibility ATVBAHA.117.309751. that VPS34 may influence platelet ROS generation and aggregation 2. Dharmarajah J, Arthur JF, Sobey CG, Drummond GR. The anti-platelet through a NADPH oxidase-independent pathway. effects of apocynin in mice are not mediated by inhibition of NADPH The role of NADPH oxidase in ROS-dependent platelet acti- oxidase activity. Naunyn Schmiedebergs Arch Pharmacol. 2010;382:377– 2–4 vation and aggregation is controversial. Platelets are known to 384. doi: 10.1007/s00210-010-0552-3. 1–8 3. Walsh TG, Berndt MC, Carrim N, Cowman J, Kenny D, Metharom P. The express NADPH oxidases, which assemble from cytoplasmic role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus subunits (p47phox, p67phox, p40phox, and Rac1/2) and membrane formation. Redox Biol. 2014;2:178–186. doi: 10.1016/j.redox.2013.12.023. subunits (Nox2 and p22phox). Several studies have demonstrated 4. Delaney MK, Kim K, Estevez B, Xu Z, Stojanovic-Terpo A, Shen B, that apocynin, a nonspecific inhibitor of NADPH oxidase subunit Ushio-Fukai M, Cho J, Du X. Differential roles of the NADPH-oxidase 1 6,10 and 2 in platelet activation and thrombosis. Arterioscler Thromb Vasc Biol. assembly, prevents platelet ROS generation and aggregation, 4 2016;36:846–854. doi: 10.1161/ATVBAHA.116.307308. and Delaney et al recently reported that deficiency of Nox2 within 5. Seno T, Inoue N, Gao D, Okuda M, Sumi Y, Matsui K, Yamada S, Hirata platelets leads to decreased superoxide generation and aggregation. KI, Kawashima S, Tawa R, Imajoh-Ohmi S, Sakurai H, Yokoyama M. However, other studies have questioned the importance of NADPH Involvement of NADH/NADPH oxidase in human platelet ROS produc- tion. Thromb Res. 2001;103:399–409. oxidase in platelet ROS production, activation, and aggregation. For 2 6. Chlopicki S, Olszanecki R, Janiszewski M, Laurindo FR, Panz example, Dharmarajah et al observed that platelets isolated from T, Miedzobrodzki J. Functional role of NADPH oxidase in acti- mice lacking NADPH oxidase subunits such as Nox2 or p47Phox vation of platelets. Antioxid Redox Signal. 2004;6:691–698. doi: exhibited aggregation responses to thrombin and collagen that were 10.1089/1523086041361640. similar to platelets from wild-type mice. Additionally, they showed 7. Dayal S, Wilson KM, Motto DG, Miller FJ Jr, Chauhan AK, Lentz SR. Hydrogen peroxide promotes aging-related platelet hyperactiva- that apocynin-inhibited platelet aggregation to a similar extent in tion and thrombosis. Circulation. 2013;127:1308–1316. doi: 10.1161/ platelets from wild-type and NADPH oxidase–deficient mice. CIRCULATIONAHA.112.000966. Similar results were obtained by Walsh et al, who found that plate- 8. McCarty OJ, Larson MK, Auger JM, Kalia N, Atkinson BT, Pearce AC, lets from Nox2-deficient mice were not impaired in platelet ROS Ruf S, Henderson RB, Tybulewicz VL, Machesky LM, Watson SP. Rac1 is essential for platelet lamellipodia formation and aggregate stability under generation, activation, or aggregation responses. The explanation flow. J Biol Chem. 2005;280:39474–39484. doi: 10.1074/jbc.M504672200. for these discrepant findings in murine models is not yet under - 9. Lassègue B, Griendling KK. NADPH oxidases: functions and pathologies stood, but it is noteworthy that platelets from human patients with in the vasculature. Arterioscler Thromb Vasc Biol. 2010;30:653–661. doi: chronic granulomatous disease (a genetic disorder characterized by 10.1161/ATVBAHA.108.181610. 11,12 deficiency of Nox2) also exhibit normal aggregation responses. 10. Begonja AJ, Gambaryan S, Geiger J, Aktas B, Pozgajova M, Nieswandt B, Walter U. Platelet NAD(P)H-oxidase-generated ROS production regulates In light of these observations, it is possible that loss of VPS34 af- alphaIIbbeta3-integrin activation independent of the NO/cGMP pathway. fects platelet ROS generation and aggregation responses through Blood. 2005;106:2757–2760. doi: 10.1182/blood-2005-03-1047. pathways that are independent from NADPH oxidase assembly. 11. Pignatelli P, Carnevale R, Di Santo S, Bartimoccia S, Sanguigni V, As noted by Liu et al, both VPS34 and NADPH oxidases may Lenti L, Finocchi A, Mendolicchio L, Soresina AR, Plebani A, Violi F. represent attractive targets for antithrombotic therapeutics. Therefore, Inherited human gp91phox deficiency is associated with impaired isopros- tane formation and platelet dysfunction. Arterioscler Thromb Vasc Biol. it will be important in future studies to define the specific downstream 2011;31:423–434. doi: 10.1161/ATVBAHA.110.217885. pathways of VPS34 signaling leading to platelet activation, perhaps by 12. Pignatelli P, Sanguigni V, Lenti L, Ferro D, Finocchi A, Rossi P, Violi using genetic or pharmacological approaches to inhibit VPS34 in plate- F. gp91phox-dependent expression of platelet CD40 ligand. Circulation. lets from mice deficient in Nox2 and other NADPH oxidase subunits. 2004;110:1326–1329. doi: 10.1161/01.CIR.0000134963.77201.55. (Arterioscler Thromb Vasc Biol. 2018;38:e25. DOI: 10.1161/ATVBAHA.117.310686.) © 2018 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.117.310686 e25

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Arteriosclerosis, Thrombosis, and Vascular BiologyWolters Kluwer Health

Published: Mar 1, 2018

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