Cross-Talk between NADPH Oxidase and Mitochondria: Role in ROS Signaling and Angiogenesis

Cells - Tập 9 Số 8 - Trang 1849
Tohru Fukai1,2, Masuko Ushio‐Fukai3,2
1Charlie Norwood Veterans Affairs Medical Center, Augusta GA 30901, USA
2Vascular Biology Center, Departments of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
3Department of Medicine (Cardiology), Medical College of Georgia at Augusta University, Augusta, GA 30912, USA

Tóm tắt

Angiogenesis, a new vessel formation from the pre-existing ones, is essential for embryonic development, wound repair and treatment of ischemic heart and limb diseases. However, dysregulated angiogenesis contributes to various pathologies such as diabetic retinopathy, atherosclerosis and cancer. Reactive oxygen species (ROS) derived from NADPH oxidase (NOX) as well as mitochondria play an important role in promoting the angiogenic switch from quiescent endothelial cells (ECs). However, how highly diffusible ROS produced from different sources and location can communicate with each other to regulate angiogenesis remains unclear. To detect a localized ROS signal in distinct subcellular compartments in real time in situ, compartment-specific genetically encoded redox-sensitive fluorescence biosensors have been developed. Recently, the intercellular communication, “cross-talk”, between ROS derived from NOX and mitochondria, termed “ROS-induced ROS release”, has been proposed as a mechanism for ROS amplification at distinct subcellular compartments, which are essential for activation of redox signaling. This “ROS-induced ROS release” may represent a feed-forward mechanism of localized ROS production to maintain sustained signaling, which can be targeted under pathological conditions with oxidative stress or enhanced to promote therapeutic angiogenesis. In this review, we summarize the recent knowledge regarding the role of the cross-talk between NOX and mitochondria organizing the sustained ROS signaling involved in VEGF signaling, neovascularization and tissue repair.

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Tài liệu tham khảo

Carmeliet, 2011, Molecular mechanisms and clinical applications of angiogenesis, Nature, 473, 298, 10.1038/nature10144

Simons, 2016, Mechanisms and regulation of endothelial VEGF receptor signalling, Nat. Rev. Mol. Cell Biol., 17, 611, 10.1038/nrm.2016.87

Simons, 2012, An inside view: VEGF receptor trafficking and signaling, Physiology (Bethesda), 27, 213

Griendling, 2000, NAD(P)H oxidase: Role in cardiovascular biology and disease, Circ. Res., 86, 494, 10.1161/01.RES.86.5.494

Finkel, 2011, Signal transduction by reactive oxygen species, J. Cell Biol., 194, 7, 10.1083/jcb.201102095

2006, Localizing NADPH oxidase-derived ROS, Science STIKE, 349, re8

Terada, 2006, Specificity in reactive oxidant signaling: Think globally, act locally, J. Cell Biol., 174, 615, 10.1083/jcb.200605036

2009, Compartmentalization of redox signaling through NADPH oxidase-derived ROS, Antioxid. Redox Signal., 11, 1289, 10.1089/ars.2008.2333

Chen, 2009, Downstream targets and intracellular compartmentalization in Nox signaling, Antioxid. Redox Signa.l, 11, 2467, 10.1089/ars.2009.2594

Zhang, 2007, Mitochondrial reactive oxygen species-mediated signaling in endothelial cells, Am. J. Physiol. Heart Circ. Physiol., 292, H2023, 10.1152/ajpheart.01283.2006

Finkel, 2012, Signal transduction by mitochondrial oxidants, J. Biol. Chem., 287, 4434, 10.1074/jbc.R111.271999

Chandel, 2015, Evolution of Mitochondria as Signaling Organelles, Cell Metab., 22, 204, 10.1016/j.cmet.2015.05.013

Kim, 2017, ROS-induced ROS release orchestrated by Nox4, Nox2, and mitochondria in VEGF signaling and angiogenesis, Am. J. Physiol. Cell Physiol., 312, C749, 10.1152/ajpcell.00346.2016

Zorov, 2000, Reactive oxygen species (ROS)-induced ROS release: A new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes, J. Exp. Med., 192, 1001, 10.1084/jem.192.7.1001

Zinkevich, 2011, ROS-induced ROS release in vascular biology: Redox-redox signaling, Am. J. Physiol. Heart Circ. Physiol., 301, H647, 10.1152/ajpheart.01271.2010

Li, 2001, H(2)O(2)-induced O(2) production by a non-phagocytic NAD(P)H oxidase causes oxidant injury, J. Biol. Chem., 276, 29251, 10.1074/jbc.M102124200

Kuzkaya, 2003, Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: Implications for uncoupling endothelial nitric-oxide synthase, J. Biol. Chem., 278, 22546, 10.1074/jbc.M302227200

Radi, 2002, Peroxynitrite reactions and formation in mitochondria, Free Radic. Biol. Med., 33, 1451, 10.1016/S0891-5849(02)01111-5

Dikalov, 2011, Cross talk between mitochondria and NADPH oxidases, Free Radic. Biol. Med., 51, 1289, 10.1016/j.freeradbiomed.2011.06.033

Daiber, 2010, Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species, Biochim. Biophys. Acta, 1797, 897, 10.1016/j.bbabio.2010.01.032

Kim, 2014, Oxidative stress in angiogenesis and vascular disease, Blood, 123, 625, 10.1182/blood-2013-09-512749

Aldosari, S., Awad, M., Harrington, E.O., Sellke, F.W., and Abid, M.R. (2018). Subcellular Reactive Oxygen Species (ROS) in Cardiovascular Pathophysiology. Antioxidants (Basel), 7.

Zinkevich, 2017, Roles of NADPH oxidase and mitochondria in flow-induced vasodilation of human adipose arterioles: ROS-induced ROS release in coronary artery disease, Microcirculation, 24, e12380, 10.1111/micc.12380

Alexander, 2004, Reactive oxygen species as mediators of angiogenesis signaling: Role of NAD(P)H oxidase, Mol. Cell Biochem., 264, 85, 10.1023/B:MCBI.0000044378.09409.b5

Bochkov, 2006, Oxidized phospholipids stimulate angiogenesis via autocrine mechanisms, implicating a novel role for lipid oxidation in the evolution of atherosclerotic lesions, Circ. Res., 99, 900, 10.1161/01.RES.0000245485.04489.ee

Podrez, 2002, A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions, J. Biol. Chem., 277, 38517, 10.1074/jbc.M205924200

2006, Redox signaling in angiogenesis: Role of NADPH oxidase, Cardiovasc. Res., 71, 226, 10.1016/j.cardiores.2006.04.015

2007, VEGF signaling through NADPH oxidase-derived ROS, Antioxid. Redox Signal., 9, 731, 10.1089/ars.2007.1556

Urao, 2009, Novel role of NADPH oxidase in angiogenesis and stem/progenitor cell function, Antioxid. Redox Signal., 11, 2517, 10.1089/ars.2009.2582

Deudero, 2006, Mechanisms of endothelial response to oxidative aggression: Protective role of autologous VEGF and induction of VEGFR2 by H2O2, Am. J. Physiol. Heart Circ. Physiol., 291, H1395, 10.1152/ajpheart.01277.2005

Chua, 1998, Upregulation of vascular endothelial growth factor by H2O2 in rat heart endothelial cells, Free Radic. Biol. Med., 25, 891, 10.1016/S0891-5849(98)00115-4

Yasuda, 2000, A novel effect of polymorphonuclear leukocytes in the facilitation of angiogenesis, Life Sci., 66, 2113, 10.1016/S0024-3205(00)00537-3

Schreml, 2010, Oxygen in acute and chronic wound healing, Br. J. Derm., 163, 257, 10.1111/j.1365-2133.2010.09804.x

Knighton, 1983, Oxygen tension regulates the expression of angiogenesis factor by macrophages, Science, 221, 1283, 10.1126/science.6612342

Urao, N., Sudhahar, V., Kim, S.J., Chen, G.F., McKinney, R.D., Kojda, G., Fukai, T., and Ushio-Fukai, M. (2013). Critical role of endothelial hydrogen peroxide in post-ischemic neovascularization. PLoS ONE, 8.

Ikeda, 2005, Novel role of ARF6 in vascular endothelial growth factor-induced signaling and angiogenesis, Circ. Res., 96, 467, 10.1161/01.RES.0000158286.51045.16

Burgoyne, 2015, Deficient angiogenesis in redox-dead Cys17Ser PKARIalpha knock-in mice, Nat. Commun., 6, 7920, 10.1038/ncomms8920

Kang, 2011, Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells, Mol. Cell, 44, 545, 10.1016/j.molcel.2011.08.040

Kim, 2018, Redox Regulation of Mitochondrial Fission Protein Drp1 by Protein Disulfide Isomerase Limits Endothelial Senescence, Cell Rep., 23, 3565, 10.1016/j.celrep.2018.05.054

Brandes, 2008, Composition and functions of vascular nicotinamide adenine dinucleotide phosphate oxidases, Trends Cardiovasc. Med., 18, 15, 10.1016/j.tcm.2007.11.001

Brandes, 2014, Nox family NADPH oxidases: Molecular mechanisms of activation, Free Radic. Biol. Med., 76, 208, 10.1016/j.freeradbiomed.2014.07.046

Buvelot, 2019, Mammalian NADPH Oxidases, Methods Mol. Biol., 1982, 17, 10.1007/978-1-4939-9424-3_2

Grasberger, 2006, Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent, J. Biol. Chem., 281, 18269, 10.1074/jbc.C600095200

Lassegue, 2010, NADPH oxidases: Functions and pathologies in the vasculature, Arter. Thromb. Vasc. Biol., 30, 653, 10.1161/ATVBAHA.108.181610

Drummond, 2014, Endothelial NADPH oxidases: Which NOX to target in vascular disease?, Trends Endocrinol. Metab., 25, 452, 10.1016/j.tem.2014.06.012

Nisimoto, 2014, Nox4: A hydrogen peroxide-generating oxygen sensor, Biochemistry, 53, 5111, 10.1021/bi500331y

Takac, 2011, The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4, J. Biol. Chem., 286, 13304, 10.1074/jbc.M110.192138

Pandey, 2011, Calcium/calmodulin-dependent kinase II mediates the phosphorylation and activation of NADPH oxidase 5, Mol. Pharm., 80, 407, 10.1124/mol.110.070193

Overmyer, 2003, Reactive oxygen species and hormonal control of cell death, Trends Plant Sci., 8, 335, 10.1016/S1360-1385(03)00135-3

Bayraktutan, 2000, Molecular characterization and localization of the NAD(P)H oxidase components gp91-phox and p22-phox in endothelial cells, Arter. Thromb. Vasc. Biol., 20, 1903, 10.1161/01.ATV.20.8.1903

Lyle, 2009, Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells, Circ. Res., 105, 249, 10.1161/CIRCRESAHA.109.193722

Paredes, 2018, Poldip2 is an oxygen-sensitive protein that controls PDH and alphaKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer, Proc Natl. Acad. Sci. USA, 115, 1789, 10.1073/pnas.1720693115

Paredes, 2020, Mitochondrial Protein Poldip2 (Polymerase Delta Interacting Protein 2) Controls Vascular Smooth Muscle Differentiated Phenotype by O-Linked GlcNAc (N-Acetylglucosamine) Transferase-Dependent Inhibition of a Ubiquitin Proteasome System, Circ. Res., 126, 41, 10.1161/CIRCRESAHA.119.315932

Amanso, 2014, Polymerase delta-interacting protein 2 promotes postischemic neovascularization of the mouse hindlimb, Arter. Thromb. Vasc. Biol., 34, 1548, 10.1161/ATVBAHA.114.303873

Prior, 2016, The Endoplasmic Reticulum Chaperone Calnexin Is a NADPH Oxidase NOX4 Interacting Protein, J. Biol. Chem., 291, 7045, 10.1074/jbc.M115.710772

Wang, H., and Hartnett, M.E. (2017). Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects. Antioxidantds (Basel), 6.

Petry, 2006, NOX2 and NOX4 mediate proliferative response in endothelial cells, Antioxid. Redox Signal., 8, 1473, 10.1089/ars.2006.8.1473

Pendyala, 2009, Role of Nox4 and Nox2 in hyperoxia-induced reactive oxygen species generation and migration of human lung endothelial cells, Antioxid. Redox Signal., 11, 747, 10.1089/ars.2008.2203

Chen, 2014, Both hydrogen peroxide and transforming growth factor beta 1 contribute to endothelial Nox4 mediated angiogenesis in endothelial Nox4 transgenic mouse lines, Biochim. Biophys. Acta, 1842, 2489, 10.1016/j.bbadis.2014.10.007

Peshavariya, 2014, Transforming growth factor-beta1 requires NADPH oxidase 4 for angiogenesis in vitro and in vivo, J. Cell Mol. Med., 18, 1172, 10.1111/jcmm.12263

Zhuang, 2010, NADPH oxidase 4 mediates reactive oxygen species induction of CD146 dimerization in VEGF signal transduction, Free Radic. Biol. Med., 49, 227, 10.1016/j.freeradbiomed.2010.04.007

Wang, 2014, Endothelial NADPH oxidase 4 mediates vascular endothelial growth factor receptor 2-induced intravitreal neovascularization in a rat model of retinopathy of prematurity, Mol. Vis., 20, 231

Wang, 2014, NADPH oxidase 4 promotes cardiac microvascular angiogenesis after hypoxia/reoxygenation in vitro, Free Radic. Biol. Med., 69, 278, 10.1016/j.freeradbiomed.2014.01.027

Craige, 2015, Reactive oxygen species in endothelial function - from disease to adaptation, Circ. J., 79, 1145, 10.1253/circj.CJ-15-0464

Evangelista, 2012, Nox4- and Nox2-dependent oxidant production is required for VEGF-induced SERCA cysteine-674 S-glutathiolation and endothelial cell migration, Free Radic. Biol. Med., 53, 2327, 10.1016/j.freeradbiomed.2012.10.546

Hilenski, 2004, IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species--dependent endothelial migration and proliferation, Circ. Res., 95, 276, 10.1161/01.RES.0000136522.58649.60

Abid, 2007, NADPH oxidase activity selectively modulates vascular endothelial growth factor signaling pathways, J. Biol. Chem., 282, 35373, 10.1074/jbc.M702175200

Urao, 2008, Role of nox2-based NADPH oxidase in bone marrow and progenitor cell function involved in neovascularization induced by hindlimb ischemia, Circ. Res., 103, 212, 10.1161/CIRCRESAHA.108.176230

Craige, 2011, NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation, Circulation, 124, 731, 10.1161/CIRCULATIONAHA.111.030775

Sirker, 2011, NADPH oxidases in cardiovascular disease: Insights from in vivo models and clinical studies, Basic Res. Cardiol., 106, 735, 10.1007/s00395-011-0190-z

Schroder, 2012, Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase, Circ. Res., 110, 1217, 10.1161/CIRCRESAHA.112.267054

Chan, 2013, Involvement of Nox2 NADPH oxidase in retinal neovascularization, Investig. Ophthalmol. Vis. Sci., 54, 7061, 10.1167/iovs.13-12883

Chen, 2015, Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function, Sci. Rep., 5, 14780, 10.1038/srep14780

Vogel, 2015, Nox4 supports proper capillary growth in exercise and retina neo-vascularization, J. Physiol., 593, 2145, 10.1113/jphysiol.2014.284901

Helfinger, 2016, The NADPH Oxidase Nox4 mediates tumour angiogenesis, Acta Physiol. (Oxford), 216, 435, 10.1111/apha.12625

Rivera, 2010, Nox isoforms in vascular pathophysiology: Insights from transgenic and knockout mouse models, Redox Rep., 15, 50, 10.1179/174329210X12650506623401

Ebrahimian, 2006, NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes, Am. J. Pathol., 169, 719, 10.2353/ajpath.2006.060042

Sedeek, 2012, Oxidative stress, Nox isoforms and complications of diabetes--potential targets for novel therapies, J. Cardiovasc. Transl. Res., 5, 509, 10.1007/s12265-012-9387-2

Kahles, 2007, NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke, Stroke, 38, 3000, 10.1161/STROKEAHA.107.489765

Bendall, 2007, Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: Studies in endothelial-targeted Nox2 transgenic mice, Circ. Res., 100, 1016, 10.1161/01.RES.0000263381.83835.7b

Murdoch, 2011, Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction, Basic. Res. Cardiol., 106, 527, 10.1007/s00395-011-0179-7

Sag, 2017, Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure, Circulation, 135, 2163, 10.1161/CIRCULATIONAHA.116.023877

Chen, 2008, Regulation of ROS signal transduction by NADPH oxidase 4 localization, J. Cell Biol., 181, 1129, 10.1083/jcb.200709049

Chen, 2012, From form to function: The role of Nox4 in the cardiovascular system, Front. Physiol., 3, 412, 10.3389/fphys.2012.00412

Poole, 2004, Protein sulfenic acids in redox signaling, Annu. Rev Pharm. Toxicol., 44, 325, 10.1146/annurev.pharmtox.44.101802.121735

Ikeda, 2005, IQGAP1 regulates reactive oxygen species-dependent endothelial cell migration through interacting with Nox2, Arter. Thromb. Vasc. Biol., 25, 2295, 10.1161/01.ATV.0000187472.55437.af

Kaplan, 2011, Localized cysteine sulfenic acid formation by vascular endothelial growth factor: Role in endothelial cell migration and angiogenesis, Free Radic. Res., 45, 1124, 10.3109/10715762.2011.602073

Urao, N., Razvi, M., Oshikawa, J., McKinney, R.D., Chavda, R., Bahou, W.F., Fukai, T., and Ushio-Fukai, M. (2010). IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration. PLoS ONE, 5.

Oshikawa, J., Urao, N., Kim, H.W., Kaplan, N., Razvi, M., McKinney, R., Poole, L.B., Fukai, T., and Ushio-Fukai, M. (2010). Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLoS ONE, 5.

Go, 2008, Redox compartmentalization in eukaryotic cells, Biochim. Biophys. Acta, 1780, 1273, 10.1016/j.bbagen.2008.01.011

Kumari, 2018, Reactive Oxygen Species: A Key Constituent in Cancer Survival, Biomark. Insights, 13, 1177271918755391, 10.1177/1177271918755391

Buckingham, 2002, Topology of superoxide production from different sites in the mitochondrial electron transport chain, J. Biol. Chem., 277, 44784, 10.1074/jbc.M207217200

Han, 2003, Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol, J. Biol. Chem., 278, 5557, 10.1074/jbc.M210269200

Chandel, 2000, Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: A mechanism of O2 sensing, J. Biol. Chem., 275, 25130, 10.1074/jbc.M001914200

Klimova, 2008, Mitochondrial complex III regulates hypoxic activation of HIF, Cell Death Differ., 15, 660, 10.1038/sj.cdd.4402307

Guzy, 2005, Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing, Cell Metab., 1, 401, 10.1016/j.cmet.2005.05.001

Reichard, 2019, The role of mitochondria in angiogenesis, Mol. Biol. Rep., 46, 1393, 10.1007/s11033-018-4488-x

Wang, 2011, Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species, Am. J. Physiol. Cell Physiol., 301, C695, 10.1152/ajpcell.00322.2010

Harel, 2017, NOX2, NOX4, and mitochondrial-derived reactive oxygen species contribute to angiopoietin-1 signaling and angiogenic responses in endothelial cells, Vasc. Pharm., 92, 22, 10.1016/j.vph.2017.03.002

Diebold, 2019, Mitochondrial complex III is necessary for endothelial cell proliferation during angiogenesis, Nat. Metab., 1, 158, 10.1038/s42255-018-0011-x

Chen, 2004, Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling, J. Biol. Chem., 279, 35079, 10.1074/jbc.M404859200

Warren, 2014, A ligand-independent VEGFR2 signaling pathway limits angiogenic responses in diabetes, Sci. Signal., 7, ra1, 10.1126/scisignal.2004235

Chung, 2003, Molecular ordering of ROS production, mitochondrial changes, and caspase activation during sodium salicylate-induced apoptosis, Free Radic. Biol. Med., 34, 434, 10.1016/S0891-5849(02)01301-1

Zorov, 2006, Mitochondrial ROS-induced ROS release: An update and review, Biochim. Biophys. Acta, 1757, 509, 10.1016/j.bbabio.2006.04.029

Aon, 2006, The fundamental organization of cardiac mitochondria as a network of coupled oscillators, Biophys. J., 91, 4317, 10.1529/biophysj.106.087817

Aon, 2008, Mitochondrial oscillations in physiology and pathophysiology, Adv. Exp. Med. Biol., 641, 98, 10.1007/978-0-387-09794-7_8

Bak, 2015, Cysteine-mediated redox signalling in the mitochondria, Mol. Biosyst., 11, 678, 10.1039/C4MB00571F

Tsai, 2016, Reactive oxygen species derived from NADPH oxidase 1 and mitochondria mediate angiotensin II-induced smooth muscle cell senescence, J. Mol. Cell. Cardiol., 98, 18, 10.1016/j.yjmcc.2016.07.001

Salazar, G. (2018). NADPH Oxidases and Mitochondria in Vascular Senescence. Int. J. Mol. Sci., 19.

Dikalov, 2014, Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension, Antioxid. Redox Signal., 20, 281, 10.1089/ars.2012.4918

Steven, 2014, Molecular mechanisms of the crosstalk between mitochondria and NADPH oxidase through reactive oxygen species-studies in white blood cells and in animal models, Antioxid. Redox Signal., 20, 247, 10.1089/ars.2012.4953

Wosniak, 2009, Cross-talk between mitochondria and NADPH oxidase: Effects of mild mitochondrial dysfunction on angiotensin II-mediated increase in Nox isoform expression and activity in vascular smooth muscle cells, Antioxid Redox Signal, 11, 1265, 10.1089/ars.2009.2392

Waypa, 2010, Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells, Circ. Res., 106, 526, 10.1161/CIRCRESAHA.109.206334

Bilan, 2013, HyPer-3: A genetically encoded H(2)O(2) probe with improved performance for ratiometric and fluorescence lifetime imaging, Acs. Chem. Biol., 8, 535, 10.1021/cb300625g

Griendling, 2016, Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association, Circ. Res., 119, 5, 10.1161/RES.0000000000000110

Rezende, 2018, Detection of Hydrogen Peroxide with Fluorescent Dyes, Antioxid. Redox Signal., 29, 585, 10.1089/ars.2017.7401

Giorgi, 2009, Structural and functional link between the mitochondrial network and the endoplasmic reticulum, Int. J. Biochem. Cell Biol., 41, 1817, 10.1016/j.biocel.2009.04.010

Marchi, 2014, The endoplasmic reticulum-mitochondria connection: One touch, multiple functions, Biochim. Biophys. Acta, 1837, 461, 10.1016/j.bbabio.2013.10.015

Dang, 2009, p47phox, the phagocyte NADPH oxidase/NOX2 organizer: Structure, phosphorylation and implication in diseases, Exp. Mol. Med., 41, 217, 10.3858/emm.2009.41.4.058

Servitja, 2003, Rac1 function is required for Src-induced transformation. Evidence of a role for Tiam1 and Vav2 in Rac activation by Src, J. Biol. Chem., 278, 34339, 10.1074/jbc.M302960200

Garrett, 2007, VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2, Exp. Cell Res., 313, 3285, 10.1016/j.yexcr.2007.05.027

Giorgio, 2005, Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis, Cell, 122, 221, 10.1016/j.cell.2005.05.011

Pinton, 2007, Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc, Science, 315, 659, 10.1126/science.1135380

Oshikawa, 2012, Novel role of p66Shc in ROS-dependent VEGF signaling and angiogenesis in endothelial cells, Am. J. Physiol. Heart Circ. Physiol., 302, H724, 10.1152/ajpheart.00739.2011

Bosutti, 2007, Relation between the plasma levels of LDL-cholesterol and the expression of the early marker of inflammation long pentraxin PTX3 and the stress response gene p66ShcA in pacemaker-implanted patients, Clin. Exp. Med., 7, 16, 10.1007/s10238-007-0118-y

Shafique, 2017, Mitochondrial redox plays a critical role in the paradoxical effects of NAPDH oxidase-derived ROS on coronary endothelium, Cardiovasc. Res., 113, 234, 10.1093/cvr/cvw249