Oxidative Stress in Atherosclerosis
Tóm tắt
Atherosclerosis is now considered a chronic inflammatory disease. Oxidative stress induced by generation of excess reactive oxygen species has emerged as a critical, final common mechanism in atherosclerosis. Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. Although essential for vascular homeostasis, uncontrolled production of ROS is implicated in vascular injury. Endogenous anti-oxidants function as checkpoints to avoid these untoward consequences of ROS, and an imbalance in the oxidant/anti-oxidant mechanisms leads to a state of oxidative stress. In this review, we discuss the role of ROS and anti-oxidant mechanisms in the development and progression of atherosclerosis, the role of oxidized low-density lipoprotein cholesterol, and highlight potential anti-oxidant therapeutic strategies relevant to atherosclerosis. There is growing evidence on how traditional risk factors translate into oxidative stress and contribute to atherosclerosis. Clinical trials evaluating anti-oxidant supplements had failed to improve atherosclerosis. Current studies focus on newer ROS scavengers that specifically target mitochondrial ROS, newer nanotechnology-based drug delivery systems, gene therapies, and anti-miRNAs. Synthetic LOX-1 modulators that inhibit the effects of Ox-LDL are currently in development. Research over the past few decades has led to identification of multiple ROS generating systems that could potentially be modulated in atherosclerosis. Therapeutic approaches currently being used for atheroslcerotic vascular disease such as aspirin, statins, and renin-angiotensin system inhibitors exert a pleiotropic antioxidative effects. There is ongoing research to identify novel therapeutic modalities to selectively target oxidative stress in atherosclerosis.
Tài liệu tham khảo
Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12(3):204–12.
Peluso I, Morabito G, Urban L, Ioannone F, Serafini M. Oxidative stress in atherosclerosis development: the central role of LDL and oxidative burst. Endocr Metab Immune Disord Drug Targets. 2012;12(4):351–60.
Zhang DX, Gutterman DD. Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol. 2007;292(5):2023.
•• Förstermann U, Xia N, Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res. 2017;120(4):713–35. This review discusses the role of ROS generators in vascular wall include NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, xanthine oxidase, the mitochondrial electron transport chain, and uncoupled endothelial nitric oxide (NO) synthase in the pathogenesis of atherosclerosis
Ketelhuth DFJ, Hansson GK. Cellular immunity, low-density lipoprotein and atherosclerosis: break of tolerance in the artery wall. Thromb Haemost. 2011 Nov;106(5):779–86.
Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868–74.
Drummond GR, Selemidis S, Griendling KK, Sobey CG. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov. 2011;10(6):453–71.
Lassègue B, Sorescu D, Szöcs K, Yin Q, Akers M, Zhang Y, et al. Novel gp91 (phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res. 2001;88(9):888–94.
Görlach A, Brandes RP, Nguyen K, Amidi M, Dehghani F, Busse R. A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall. Circ Res. 2000;87(1):26–32.
Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, et al. Nox4 As the major catalytic component of an endothelial NAD(P)H oxidase. Circulation. 2004;109(2):227–33.
Takac I, Schröder K, Zhang L, Lardy B, Anilkumar N, Lambeth JD, et al. The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem. 2011;286(15):13304–13.
Guzik TJ, Chen W, Gongora MC, Guzik B, Lob HE, Mangalat D, et al. Calcium-dependent NOX5 nicotinamide adenine dinucleotide phosphate oxidase contributes to vascular oxidative stress in human coronary artery disease. J Am Coll Cardiol. 2008;52(22):1803–9.
Yu P, Han W, Villar VAM, Yang Y, Lu Q, Lee H, et al. Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells. Redox Biol. 2014;2:570–9.
Holterman CE, Thibodeau J, Towaij C, Gutsol A, Montezano AC, Parks RJ, et al. Nephropathy and elevated BP in mice with podocyte-specific NADPH oxidase 5 expression. J Am Soc Nephrol. 2014;25(4):784–97.
Vendrov AE, Hakim ZS, Madamanchi NR, Rojas M, Madamanchi C, Runge MS. Atherosclerosis is attenuated by limiting superoxide generation in both macrophages and vessel wall cells. Arterioscler Thromb Vasc Biol. 2007;27(12):2714–21.
Patetsios P, Song M, Shutze WP, Pappas C, Rodino W, Ramirez JA, et al. Identification of uric acid and xanthine oxidase in atherosclerotic plaque. Am J Cardiol. 2001;88(2):191, A6.
McNally JS, Davis ME, Giddens DP, Saha A, Hwang J, Dikalov S, et al. Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol. 2003;285(6):2290.
Landmesser U, Spiekermann S, Preuss C, Sorrentino S, Fischer D, Manes C, et al. Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease. Arterioscler Thromb Vasc Biol. 2007;27(4):943–8.
Guthikonda S, Sinkey C, Barenz T, Haynes WG. Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation. 2003;107(3):416–21.
Schröder K, Vecchione C, Jung O, Schreiber JG, Shiri-Sverdlov R, van Gorp PJ, et al. Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in Apo E knockout mice fed a western-type diet. Free Radic Biol Med. 2006;41(9):1353–60.
Dai Y, Cao Y, Zhang Z, Vallurupalli S, Mehta JL. Xanthine oxidase induces foam cell formation through LOX-1 and NLRP3 activation. Cardiovasc Drugs Ther. 2017;31(1):19–27.
Lin H, Daimon M, Wang C, Ho Y, Uang Y, Chiang S, et al. Allopurinol, benzbromarone and risk of coronary heart disease in gout patients: a population-based study. Int J Cardiol. 2017;233:85–90.
Madamanchi NR, Runge MS. Mitochondrial dysfunction in atherosclerosis. Circ Res. 2007;100(4):460–73.
Cervantes Gracia K, Llanas-Cornejo D, Husi H. CVD and Oxidative Stress. J Clin Med. 2017;6(2):22.
Bäck M, Hansson GK. Leukotriene receptors in atherosclerosis. Ann Med. 2006;38(7):493–502.
Adamek A, Jung S, Dienesch C, Laser M, Ertl G, Bauersachs J, et al. Role of 5-lipoxygenase in myocardial ischemia-reperfusion injury in mice. Eur J Pharmacol. 2007;571(1):51–4.
Suzuki H, Kayama Y, Sakamoto M, Iuchi H, Shimizu I, Yoshino T, et al. Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy. Diabetes. 2015;64(2):618–30.
Hawkins CL. The role of hypothiocyanous acid (HOSCN) in biological systems. Free Radic Res. 2009;43(12):1147–58.
Baldus S, Heitzer T, Eiserich JP, Lau D, Mollnau H, Ortak M, et al. Myeloperoxidase enhances nitric oxide catabolism during myocardial ischemia and reperfusion. Free Radic Biol Med. 2004;37(6):902–11.
Exner M, Hermann M, Hofbauer R, Hartmann B, Kapiotis S, Gmeiner B. Thiocyanate catalyzes myeloperoxidase-initiated lipid oxidation in LDL. Free Radic Biol Med. 2004;37(2):146–55.
Bergt C, Pennathur S, Fu X, Byun J, O'Brien K, McDonald TO, et al. The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Proc Natl Acad Sci U S A. 2004;101(35):13032–7.
Salonen I, Huttunen K, Hirvonen M, Dufva J, Groundstroem K, Dufva H, et al. Serum myeloperoxidase is independent of the risk factors of atherosclerosis. Coron Artery Dis. 2012;23(4):251–8.
Antoniades C, Shirodaria C, Crabtree M, Rinze R, Alp N, Cunnington C, et al. Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation. Circulation. 2007;116(24):2851–9.
Ueda S, Matsuoka H, Miyazaki H, Usui M, Okuda S, Imaizumi T. Tetrahydrobiopterin restores endothelial function in long-term smokers. J Am Coll Cardiol. 2000;35(1):71–5.
Li H, Horke S, Förstermann U. Oxidative stress in vascular disease and its pharmacological prevention. Trends Pharmacol Sci. 2013;34(6):313–9.
Yang H, Roberts LJ, Shi MJ, Zhou LC, Ballard BR, Richardson A, et al. Retardation of atherosclerosis by overexpression of catalase or both cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E. Circ Res. 2004;95(11):1075–81.
Cheng F, Torzewski M, Degreif A, Rossmann H, Canisius A, Lackner KJ. Impact of glutathione peroxidase-1 deficiency on macrophage foam cell formation and proliferation: implications for atherogenesis. PLoS One. 2013;8(8):e72063.
Guo Z, Ran Q, Roberts LJ, Zhou L, Richardson A, Sharan C, et al. Suppression of atherogenesis by overexpression of glutathione peroxidase-4 in apolipoprotein E-deficient mice. Free Radic Biol Med. 2008;44(3):343–52.
Tward A, Xia Y, Wang X, Shi Y, Park C, Castellani LW, et al. Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation. 2002;106(4):484–90.
Ng CJ, Hama SY, Bourquard N, Navab M, Reddy ST. Adenovirus mediated expression of human paraoxonase 2 protects against the development of atherosclerosis in apolipoprotein E-deficient mice. Mol Genet Metab. 2006;89(4):368–73.
Marsillach J, Camps J, Beltran-Debón R, Rull A, Aragones G, Maestre-Martínez C, et al. Immunohistochemical analysis of paraoxonases-1 and 3 in human atheromatous plaques. Eur J Clin Investig. 2011;41(3):308–14.
Shih DM, Yu JM, Vergnes L, Dali-Youcef N, Champion MD, Devarajan A, et al. PON3 Knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis. FASEB J. 2015-4;29(4):1185–97.
Chen B, Wang W, Shen T, Qi R. Thioredoxin 1 downregulates oxidized low-density lipoprotein-induced adhesion molecule expression via Smad 3 protein. PLoS One. 2013;8(9):e76226.
Kirsch J, Schneider H, Pagel J, Rehberg M, Singer M, Hellfritsch J, et al. Endothelial dysfunction, and a Prothrombotic, Proinflammatory phenotype is caused by loss of mitochondrial Thioredoxin reductase in endothelium. Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1891–9.
Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33(7):837d.
Kuhlencordt PJ, Gyurko R, Han F, Scherrer-Crosbie M, Aretz TH, Hajjar R, et al. Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation. 2001;104(4):448–54.
Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87(1):315–424.
Guzik TJ, Sadowski J, Guzik B, Jopek A, Kapelak B, Przybylowski P, et al. Coronary artery superoxide production and nox isoform expression in human coronary artery disease. Arterioscler Thromb Vasc Biol. 2006;26(2):333–9.
Steffen Y, Vuillaume G, Stolle K, Roewer K, Lietz M, Schueller J, et al. Cigarette smoke and LDL cooperate in reducing nitric oxide bioavailability in endothelial cells via effects on both eNOS and NADPH oxidase. Nitric Oxide. 2012;27(3):176–84.
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058–70.
Li H, Förstermann U. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol. 2013;13(2):161–7.
Jaimes EA, DeMaster EG, Tian R, Raij L. Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation. Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1031–6.
Hwang J, Ing MH, Salazar A, Lassègue B, Griendling K, Navab M, et al. Pulsatile versus oscillatory shear stress regulates NADPH oxidase subunit expression: implication for native LDL oxidation. Circ Res. 2003;93(12):1225–32.
De Keulenaer GW, Chappell DC, Ishizaka N, Nerem RM, Alexander RW, Griendling KK. Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase. Circ Res. 1998;82(10):1094–101.
Mehta JL. Oxidized or native low-density lipoprotein cholesterol⁎editorials published in the journal of American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology. J Am Coll Cardiol. 2006;48(5):980–2.
Goyal T, Mitra S, Khaidakov M, Wang X, Singla S, Ding Z, et al. Current concepts of the role of oxidized LDL receptors in atherosclerosis. Curr Atheroscler Rep. 2012;14(2):150-9.
Mehta JL, Sanada N, Hu CP, Chen J, Dandapat A, Sugawara F, et al. Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. Circ Res. 2007;100(11):1634–42.
Xu S, Ogura S, Chen J, Little PJ, Moss J, Liu P. LOX-1 in atherosclerosis: biological functions and pharmacological modifiers. Cell Mol Life Sci. 2013;70(16):2859–72.
Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386(6620):73–7.
Chen J, Zhou S, Tan Z. Aspirin and pravastatin reduce lectin-like oxidized low density lipoprotein receptor-1 expression, adhesion molecules and oxidative stress in human coronary artery endothelial cells. Chin Med J. 2010;123(12):1553–6.
Li D, Mehta JL. Antisense to LOX-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells. Circulation. 2000;101(25):2889–95.
Li D, Mehta JL. Intracellular signaling of LOX-1 in endothelial cell apoptosis. Circ Res. 2009;104(5):566–8.
Ryoo S, Bhunia A, Chang F, Shoukas A, Berkowitz DE, Romer LH. OxLDL-dependent activation of arginase II is dependent on the LOX-1 receptor and downstream rho a signaling. Atherosclerosis. 2011;214(2):279–87.
Shi Y, Cosentino F, Camici GG, Akhmedov A, Vanhoutte PM, Tanner FC, et al. Oxidized low-density lipoprotein activates p66Shc via lectin-like oxidized low-density lipoprotein receptor-1, protein kinase C-beta, and c-Jun N-terminal kinase kinase in human endothelial cells. Arterioscler Thromb Vasc Biol. 2011;31(9):2090–7.
Spescha RD, Glanzmann M, Simic B, Witassek F, Keller S, Akhmedov A, et al. Adaptor protein p 66(Shc) mediates hypertension-associated, cyclic stretch-dependent, endothelial damage. Hypertension. 2014;64(2):347–53.
Schaeffer DF, Riazy M, Parhar KS, Chen JH, Duronio V, Sawamura T, et al. LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasma. J Lipid Res. 2009;50(8):1676–84.
Pirillo A, Norata GD, Catapano AL. LOX-1, OxLDL, and atherosclerosis. Mediat Inflamm. 2013;2013. https://doi.org/10.1155/2013/152786.
Hinagata J, Kakutani M, Fujii T, Naruko T, Inoue N, Fujita Y, et al. Oxidized LDL receptor LOX-1 is involved in neointimal hyperplasia after balloon arterial injury in a rat model. Cardiovasc Res. 2006;69(1):263–71.
Hu C, Dandapat A, Sun L, Chen J, Marwali MR, Romeo F, et al. LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high-cholesterol diet. Cardiovasc Res. 2008;79(2):287–93.
Li D, Liu L, Chen H, Sawamura T, Ranganathan S, Mehta JL. LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells. Circulation. 2003;107(4):612–7.
Li L, Renier G. The oral anti-diabetic agent, gliclazide, inhibits oxidized LDL-mediated LOX-1 expression, metalloproteinase-9 secretion and apoptosis in human aortic endothelial cells. Atherosclerosis. 2009;204(1):40–6.
Hsieh CC, Yen MH, Yen CH, Lau YT. Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells. Cardiovasc Res. 2001;49(1):135–45.
Kume N, Kita T. Apoptosis of vascular cells by oxidized LDL: involvement of caspases and LOX-1 and its implication in atherosclerotic plaque rupture. Circ Res. 2004;94(3):269–70.
Marwali MR, Hu C, Mohandas B, Dandapat A, Deonikar P, Chen J, et al. Modulation of ADP-induced platelet activation by aspirin and pravastatin: role of lectin-like oxidized low-density lipoprotein receptor-1, nitric oxide, oxidative stress, and inside-out integrin signaling. J Pharmacol Exp Ther. 2007;322(3):1324–32.
Sakurai K, Cominacini L, Garbin U, Fratta Pasini A, Sasaki N, Takuwa Y, et al. Induction of endothelin-1 production in endothelial cells via co-operative action between CD40 and lectin-like oxidized LDL receptor (LOX-1). J Cardiovasc Pharmacol. 2004;44(Suppl 1):173.
Cominacini L, Fratta Pasini A, Garbin U, Pastorino A, Rigoni A, Nava C, et al. The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells. J Am Coll Cardiol. 2003;41(3):499–507.
Wyche KE, Wang SS, Griendling KK, Dikalov SI, Austin H, Rao S, et al. C242T CYBA polymorphism of the NADPH oxidase is associated with reduced respiratory burst in human neutrophils. Hypertension. 2004;43(6):1246–51.
Xu Q, Yuan F, Shen X, Wen H, Li W, Cheng B, et al. Polymorphisms of C242T and A640G in CYBA gene and the risk of coronary artery disease: a meta-analysis. PLoS One. 2014;9(1):e84251.
Neves AL, Mohammedi K, Emery N, Roussel R, Fumeron F, Marre M, et al. Allelic variations in superoxide dismutase-1 (SOD1) gene and renal and cardiovascular morbidity and mortality in type 2 diabetic subjects. Mol Genet Metab. 2012;106(3):359–65.
Fujimoto H, Taguchi J, Imai Y, Ayabe S, Hashimoto H, Kobayashi H, et al. Manganese superoxide dismutase polymorphism affects the oxidized low-density lipoprotein-induced apoptosis of macrophages and coronary artery disease. Eur Heart J. 2008;29(10):1267–74.
Juul K, Tybjaerg-Hansen A, Marklund S, Heegaard NHH, Steffensen R, Sillesen H, et al. Genetically reduced antioxidative protection and increased ischemic heart disease risk: the Copenhagen City heart study. Circulation. 2004;109(1):59–65.
Zhang J, Wang Z, Zhang J, Zhu L, Gao X, Chen S. Association of glutathione peroxidase-1 (GPx-1) rs1050450 Pro198Leu and Pro197Leu polymorphisms with cardiovascular risk: a meta-analysis of observational studies. J Geriatr Cardiol. 2014;11(2):141–50.
Souiden Y, Mallouli H, Meskhi S, Chaabouni Y, Rebai A, Chéour F, et al. MnSOD and GPx1 polymorphism relationship with coronary heart disease risk and severity. Biol Res. 2016;49:22.
Forsberg L, de Faire U, Marklund SL, Andersson PM, Stegmayr B, Morgenstern R. Phenotype determination of a common pro-Leu polymorphism in human glutathione peroxidase 1. Blood Cells Mol Dis. 2000;26(5):423–6.
Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A, et al. Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation. 2001;103(6):799–805.
Oak J, Cai H. Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice. Diabetes. 2007;56(1):118–26.
Wenzel P, Schulz E, Oelze M, Müller J, Schuhmacher S, Alhamdani MSS, et al. AT1-Receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats. Free Radic Biol Med. 2008;45(5):619–26.
Imanishi T, Ikejima H, Tsujioka H, Kuroi A, Kobayashi K, Muragaki Y, et al. Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability. Hypertension. 2008;51(3):734–41.
Chen B, Zhao J, Zhang S, Wu W, Qi R. Aspirin inhibits the production of reactive oxygen species by downregulating Nox4 and inducible nitric oxide synthase in human endothelial cells exposed to oxidized low-density lipoprotein. J Cardiovasc Pharmacol. 2012;59(5):405–12.
Mehta JL, Chen J, Yu F, Li DY. Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc Res. 2004;64(2):243–9.
Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012;18(11):1519–30.
Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation. 2005;111(18):2356–63.
Carrepeiro MM, Rogero MM, Bertolami MC, Botelho PB, Castro N, Castro IA. Effect of n-3 fatty acids and statins on oxidative stress in statin-treated hypercholestorelemic and normocholesterolemic women. Atherosclerosis. 2011;217(1):171–8.
Antoniades C, Bakogiannis C, Tousoulis D, Reilly S, Zhang M, Paschalis A, et al. Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity. Circulation. 2010;122(11 Suppl):66.
Oppermann M, Balz V, Adams V, Dao VT, Bas M, Suvorava T, et al. Pharmacological induction of vascular extracellular superoxide dismutase expression in vivo. J Cell Mol Med. 2009;13(7):1271–8.
Schuhmacher S, Oelze M, Bollmann F, Kleinert H, Otto C, Heeren T, et al. Vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetranitrate but not isosorbide-5-mononitrate therapy. Diabetes. 2011;60(10):2608–16.
Li H, Xia N, Förstermann U. Cardiovascular effects and molecular targets of resveratrol. Nitric Oxide. 2012;26(2):102–10.
Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang H, Losonczy G, et al. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. 2009;297(1):13.
Xia N, Daiber A, Habermeier A, Closs EI, Thum T, Spanier G, et al. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J Pharmacol Exp Ther. 2010;335(1):149–54.
Price NL, Gomes AP, Ling AJY, Duarte FV, Martin-Montalvo A, North BJ, et al. SIRT1 Is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15(5):675–90.
Oelze M, Daiber A, Brandes RP, Hortmann M, Wenzel P, Hink U, et al. Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats. Hypertension. 2006;48(4):677–84.
Mollnau H, Schulz E, Daiber A, Baldus S, Oelze M, August M, et al. Nebivolol prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits NADPH oxidase activity in inflammatory cells. Arterioscler Thromb Vasc Biol. 2003;23(4):615–21.
Münzel T, Gori T. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol. 2009;54(16):1491–9.
Smith RAJ, Murphy MP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci. 2010;1201:96–103.
• Mercer JR, Yu E, Figg N, Cheng K, Prime TA, Griffin JL, et al. The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/−/ApoE−/− mice. Free Radic Biol Med. 2012;52(5):841–9. This study demonstrates the effect of MitoQ on atherosclerotic plaque and in inhibition of features of metabolic syndrome, hence suggesting a therapeutic role for mitochondria-targeted antioxidants.
• Deshpande D, Kethireddy S, Janero DR, Amiji MM. Therapeutic efficacy of an ω-3-fatty acid-containing 17-β estradiol Nano-delivery system against experimental atherosclerosis. PLoS One. 2016;11(2):e0147337. This study demonstrates the therapeutic potential of a novel, 17-βE-loaded, CREKA-peptide-modified nano emulsion system against atherosclerosis. It was shown to reduce lesion size, lower the levels of circulating plasma lipids and decrease the gene expression of inflammatory markers associated with atherosclerosis
Bräsen JH, Leppänen O, Inkala M, Heikura T, Levin M, Ahrens F, et al. Extracellular superoxide dismutase accelerates endothelial recovery and inhibits in-stent restenosis in stented atherosclerotic Watanabe heritable hyperlipidemic rabbit aorta. J Am Coll Cardiol. 2007;50(23):2249–53.
Alp NJ, McAteer MA, Khoo J, Choudhury RP, Channon KM. Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice. Arterioscler Thromb Vasc Biol. 2004;24(3):445–50.
• Wang B, Qian H, Yang H, Xu L, Xu W, Yan J. Regression of atherosclerosis plaques in apolipoprotein E−/− mice after lentivirus-mediated RNA interference of CD40. Int J Cardiol. 2013;163(1):34–9. This study demonstrated the ability of lentivirus-mediated RNA interference technique in decreasing lipid content and increasing collagen content of atherosclerotic plaques, thereby decreasing lumen stenosis .
Kowalski PS, Lintermans LL, Morselt HWM, Leus NGJ, Ruiters MHJ, Molema G, et al. Anti-VCAM-1 and anti-E-selectin SAINT-O-Somes for selective delivery of siRNA into inflammation-activated primary endothelial cells. Mol Pharm. 2013;10(8):3033–44.
•• Pothineni NVK, Karathanasis SK, Ding Z, Arulandu A, Varughese KI, Mehta JL. LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation. J Am Coll Cardiol. 2017;69(22):2759–68. This review discusses the discovery and genetics of LOX-1, describes existing evidence supporting the role of LOX-1 in atherogenesis and summarizes LOX-1 modulation by natural and synthetic biologic compounds that could be of therapeutic use