Emerging role of oxidative stress in metabolic syndrome and cardiovascular diseases: Important role of Rac/NADPH oxidase

Journal of Pathology

Volumn 231, Issue 3, 2013, Pages 290-300

  Elnakish, Mohammad T ^a,b   Hassanain, Hamdy H ^b   Janssen, Paul M ^a,b   Angelos, Mark G ^a,b   Khan, Mahmood ^a,b  

^a OHIO STATE UNIVERSITY   (United States)

^b THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER   (United States)

Author keywords

cardiovascular disease; metabolic syndrome; oxidative stress

Indexed keywords

ACETYLCYSTEINE; ANTIOXIDANT; CYTOCHROME B; NITRIC OXIDE SYNTHASE; RAC1 PROTEIN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 2;

ARTICLE; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; COMPLEX FORMATION; CYTOSOL; DIABETES MELLITUS; HEART ARRHYTHMIA; HEART ATRIUM FIBRILLATION; HEART FAILURE; HEART MUSCLE ISCHEMIA; HUMAN; HYPERTENSION; METABOLIC SYNDROME X; NONHUMAN; OBESITY; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; REPERFUSION INJURY; RISK FACTOR;

CARDIOVASCULAR DISEASE; METABOLIC SYNDROME; OXIDATIVE STRESS;

ANIMALS; ANTIOXIDANTS; CARDIOVASCULAR AGENTS; CARDIOVASCULAR DISEASES; ENZYME INHIBITORS; HUMANS; METABOLIC SYNDROME X; NADPH OXIDASE; OXIDATIVE STRESS; RAC GTP-BINDING PROTEINS; RAC1 GTP-BINDING PROTEIN; SIGNAL TRANSDUCTION;

EID: 84885391649     PISSN: 00223417     EISSN: 10969896     Source Type: Journal    
DOI: 10.1002/path.4255     Document Type: Article

References (108)

1. Paravicini TM, Touyz RM,. NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care 2008; 31 (suppl 2): S170-180.
2. Fortuno A, San Jose G, Moreno MU, et al., Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome. Diabetes 2006; 55: 209-215.
3. Sun M, Huang X, Yan Y, et al., Rac1 is a possible link between obesity and oxidative stress in Chinese overweight adolescents. Obesity (Silver Spring) 2012; 20: 2233-2240.
4. Huang PL,. Unraveling the links between diabetes, obesity, and cardiovascular disease. Circ Res 2005; 96: 1129-1131.
5. Shishehbor MH, Aviles RJ, Brennan ML, et al., Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. J Am Med Assoc 2003; 289: 1675-1680.
6. Beckman JS, Koppenol WH,. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol 1996; 271: C1424-1437.
7. Wang M, Zhang J, Walker SJ, et al., Involvement of NADPH oxidase in age-associated cardiac remodeling. J Mol Cell Cardiol 2010; 48: 765-772.
8. Maack C, Kartes T, Kilter H, et al., Oxygen free radical release in human failing myocardium is associated with increased activity of rac1-GTPase and represents a target for statin treatment. Circulation 2003; 108: 1567-1574.
9. Hassanain H, Goldschmidt-Clermont PJ,. Rac, Superoxide and Signal Transduction. Academic Press: San Diego, CA, 1999.
10. Babior BM, Lambeth JD, Nauseef W,. The neutrophil NADPH oxidase. Arch Biochem Biophys 2002; 397: 342-344.
11. DeLeo FR, Quinn MT,. Assembly of the phagocyte NADPH oxidase: molecular interaction of oxidase proteins. J Leukoc Biol 1996; 60: 677-691.
12. Selvakumar B, Hess DT, Goldschmidt-Clermont PJ, et al., Co-regulation of constitutive nitric oxide synthases and NADPH oxidase by the small GTPase Rac. FEBS Lett 2008; 582: 2195-2202.
13. Alexander CM, Landsman PB, Teutsch SM, et al., NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003; 52: 1210-1214.
14. Ford ES, Giles WH, Dietz WH,. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. J Am Med Assoc 2002; 287: 356-359.
15. Lakka HM, Laaksonen DE, Lakka TA, et al., The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc 2002; 288: 2709-2716.
16. Hansel B, Giral P, Nobecourt E, et al., Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J Clin Endocrinol Metab 2004; 89: 4963-4971.
17. Holvoet P, Kritchevsky SB, Tracy RP, et al., The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort. Diabetes 2004; 53: 1068-1073.
18. Furukawa S, Fujita T, Shimabukuro M, et al., Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761.
19. Maddux BA, See W, Lawrence JC, Jr,., et al. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of α-lipoic acid. Diabetes 2001; 50: 404-410.
20. Matsuoka T, Kajimoto Y, Watada H, et al., Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest 1997; 99: 144-150.
21. Rudich A, Tirosh A, Potashnik R, et al., Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes 1998; 47: 1562-1569.
22. Wang Z, Thurmond DC,. Mechanisms of biphasic insulin-granule exocytosis-roles of the cytoskeleton, small GTPases and SNARE proteins. J Cell Sci 2009; 122: 893-903.
23. Morgan D, Rebelato E, Abdulkader F, et al., Association of NAD(P)H oxidase with glucose-induced insulin secretion by pancreatic beta-cells. Endocrinology 2009; 150: 2197-2201.
24. Syed I, Kyathanahalli CN, Kowluru A,. Phagocyte-like NADPH oxidase generates ROS in INS 832/13 cells and rat islets: role of protein prenylation. Am J Physiol Regul Integr Comp Physiol 2011; 300: R756-762.
25. Kowluru A., Friendly, and not so friendly, roles of Rac1 in islet β cell function: lessons learnt from pharmacological and molecular biological approaches. Biochem Pharmacol 2011; 81: 965-975.
26. Subasinghe W, Syed I, Kowluru A,. Phagocyte-like NADPH oxidase promotes cytokine-induced mitochondrial dysfunction in pancreatic β cells: evidence for regulation by Rac1. Am J Physiol Regul Integr Comp Physiol 2011; 300: R12-20.
27. Syed I, Jayaram B, Subasinghe W, et al., Tiam1/Rac1 signaling pathway mediates palmitate-induced, ceramide-sensitive generation of superoxides and lipid peroxides and the loss of mitochondrial membrane potential in pancreatic β cells. Biochem Pharmacol 2010; 80: 874-883.
28. Syed I, Kyathanahalli CN, Jayaram B, et al., Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet. Diabetes 2011; 60: 2843-2852.
29. Huang X, Sun M, Li D, et al., Augmented NADPH oxidase activity and p22phox expression in monocytes underlie oxidative stress of patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2011; 91: 371-380.
30. Ebrahimian TG, Heymes C, You D, et al., NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes. Am J Pathol 2006; 169: 719-728.
31. Shen E, Li Y, Li Y, et al., Rac1 is required for cardiomyocyte apoptosis during hyperglycemia. Diabetes 2009; 58: 2386-2395.
32. Li J, Zhu H, Shen E, et al., Deficiency of rac1 blocks NADPH oxidase activation, inhibits endoplasmic reticulum stress, and reduces myocardial remodeling in a mouse model of type 1 diabetes. Diabetes 2010; 59: 2033-2042.
33. Vecchione C, Aretini A, Marino G, et al., Selective Rac-1 inhibition protects from diabetes-induced vascular injury. Circ Res 2006; 98: 218-225.
34. Shan L, Li J, Wei M, et al., Disruption of Rac1 signaling reduces ischemia-reperfusion injury in the diabetic heart by inhibiting calpain. Free Radic Biol Med 2010; 49: 1804-1814.
35. Raij L., Workshop: hypertension and cardiovascular risk factors: role of the angiotensin II-nitric oxide interaction. Hypertension 2001; 37: 767-773.
36. Touyz RM,. Oxidative stress and vascular damage in hypertension. Curr Hypertens Rep 2000; 2: 98-105.
37. Rajagopalan S, Kurz S, Munzel T, et al., Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 1996; 97: 1916-1923.
38. Wassmann S, Laufs U, Baumer AT, et al., Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 2001; 59: 646-654.
39. Nowicki PT, Flavahan S, Hassanain H, et al., Redox signaling of the arteriolar myogenic response. Circ Res 2001; 89: 114-116.
40. Hassanain HH, Gregg D, Marcelo ML, et al., Hypertension caused by transgenic overexpression of Rac1. Antioxid Redox Signal 2007; 9: 91-100.
41. Nozoe M, Hirooka Y, Koga Y, et al., Inhibition of Rac1-derived reactive oxygen species in nucleus tractus solitarius decreases blood pressure and heart rate in stroke-prone spontaneously hypertensive rats. Hypertension 2007; 50: 62-68.
42. Fujita T., Insulin resistance and salt-sensitive hypertension in metabolic syndrome. Nephrol Dial Transpl 2007; 22: 3102-3107.
43. Fujita T., Aldosterone in salt-sensitive hypertension and metabolic syndrome. J Mol Med (Berl) 2008; 86: 729-734.
44. Shibata S, Nagase M, Yoshida S, et al., Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med 2008; 14: 1370-1376.
45. de las Fuentes L, Yang W, Davila-Roman VG, et al., Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets. Eur J Hum Genet 2012; 20: 1168-1173.
46. Zalba G, Beaumont FJ, San Jose G, et al., Vascular NADH/NADPH oxidase is involved in enhanced superoxide production in spontaneously hypertensive rats. Hypertension 2000; 35: 1055-1061.
47. Weber DS, Rocic P, Mellis AM, et al., Angiotensin II-induced hypertrophy is potentiated in mice overexpressing p22phox in vascular smooth muscle. Am J Physiol Heart Circ Physiol 2005; 288: H37-42.
48. Touyz RM, Schiffrin EL,. Increased generation of superoxide by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients: role of phospholipase D-dependent NAD(P)H oxidase-sensitive pathways. J Hypertens 2001; 19: 1245-1254.
49. Vecchione C, Carnevale D, Di Pardo A, et al., Pressure-induced vascular oxidative stress is mediated through activation of integrin-linked kinase 1/βPIX/Rac-1 pathway. Hypertension 2009; 54: 1028-1034.
50. Djordjevic T, Hess J, Herkert O, et al., Rac regulates thrombin-induced tissue factor expression in pulmonary artery smooth muscle cells involving the nuclear factor-κB pathway. Antioxid Redox Signal 2004; 6: 713-720.
51. Violi F, Basili S, Nigro C, et al., Role of NADPH oxidase in atherosclerosis. Future Cardiol 2009; 5: 83-92.
52. Vendrov AE, Hakim ZS, Madamanchi NR, et al., Atherosclerosis is attenuated by limiting superoxide generation in both macrophages and vessel wall cells. Arterioscler Thromb Vasc Biol 2007; 27: 2714-2721.
53. Warnholtz A, Nickenig G, Schulz E, et al., Increased NADH-oxidase- mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 1999; 99: 2027-2033.
54. Iwai M, Chen R, Li Z, et al., Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice. Circulation 2005; 112: 1636-1643.
55. Laufs U, Wassmann S, Czech T, et al., Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: 809-814.
56. Ohkawara H, Ishibashi T, Shiomi M, et al., RhoA and Rac1 changes in the atherosclerotic lesions of WHHLMI rabbits. J Atheroscler Thromb 2009; 16: 846-856.
57. Dwivedi S, Pandey D, Khandoga AL, et al., Rac1-mediated signaling plays a central role in secretion-dependent platelet aggregation in human blood stimulated by atherosclerotic plaque. J Transl Med 2010; 8: 128.
58. Azumi H, Inoue N, Takeshita S, et al., Expression of NADH/NADPH oxidase p22phox in human coronary arteries. Circulation 1999; 100: 1494-1498.
59. Guzik TJ, Sadowski J, Guzik B, et al., Coronary artery superoxide production and nox isoform expression in human coronary artery disease. Arterioscler Thromb Vasc Biol 2006; 26: 333-339.
60. Sorescu D, Weiss D, Lassegue B, et al., Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 2002; 105: 1429-1435.
61. Sawyer DB, Siwik DA, Xiao L, et al., Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol 2002; 34: 379-388.
62. Dhalla AK, Hill MF, Singal PK,. Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol 1996; 28: 506-514.
63. Kinugawa S, Tsutsui H, Hayashidani S, et al., Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress. Circ Res 2000; 87: 392-398.
64. Zhang GX, Kimura S, Nishiyama A, et al., Cardiac oxidative stress in acute and chronic isoproterenol-infused rats. Cardiovasc Res 2005; 65: 230-238.
65. Bendall JK, Cave AC, Heymes C, et al., Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 2002; 105: 293-296.
66. Satoh M, Ogita H, Takeshita K, et al., Requirement of Rac1 in the development of cardiac hypertrophy. Proc Natl Acad Sci USA 2006; 103: 7432-7437.
67. Custodis F, Eberl M, Kilter H, et al., Association of RhoGDIα with Rac1 GTPase mediates free radical production during myocardial hypertrophy. Cardiovasc Res 2006; 71: 342-351.
68. Hingtgen SD, Tian X, Yang J, et al., Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy. Physiol Genomics 2006; 26: 180-191.
69. Takemoto M, Node K, Nakagami H, et al., Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 2001; 108: 1429-1437.
70. Elnakish MT, Awad MM, Hassona MD, et al., Cardiac remodeling caused by transgenic overexpression of a corn Rac gene. Am J Physiol Heart Circ Physiol 2011; 301: H868-880.
71. Elnakish MT, Moldovan L, Khan M, et al., Myocardial Rac1 exhibits partial involvement in thyroxin-induced cardiomyocyte hypertrophy and its inhibition is not sufficient to improve cardiac dysfunction or contractile abnormalities in mouse papillary muscles. J Cardiovasc Pharmacol 2013; 61: 536-544.
72. Lezoualc'h F, Metrich M, Hmitou I, et al., Small GTP-binding proteins and their regulators in cardiac hypertrophy. J Mol Cell Cardiol 2008; 44: 623-632.
73. Sussman MA, Welch S, Walker A, et al., Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1. J Clin Invest 2000; 105: 875-886.
74. Hassanain HH, Sharma YK, Moldovan L, et al., Plant rac proteins induce superoxide production in mammalian cells. Biochem Biophys Res Commun 2000; 272: 783-788.
75. Higuchi Y, Otsu K, Nishida K, et al., The small GTP-binding protein Rac1 induces cardiac myocyte hypertrophy through the activation of apoptosis signal-regulating kinase 1 and nuclear factor-κB. J Biol Chem 2003; 278: 20770-20777.
76. Diwan A, Dorn GW, 2nd,. Decompensation of cardiac hypertrophy: cellular mechanisms and novel therapeutic targets. Physiology (Bethesda) 2007; 22: 56-64.
77. Selvetella G, Hirsch E, Notte A, et al., Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence. Cardiovasc Res 2004; 63: 373-380.
78. Ichihara S, Noda A, Nagata K, et al., Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure. Cardiovasc Res 2006; 69: 726-735.
79. Elnakish MT, Hassona MD, Alhaj MA, et al., Rac-induced left ventricular dilation in thyroxin-treated ZmRacD transgenic mice: role of cardiomyocyte apoptosis and myocardial fibrosis. PLoS One 2012; 7: e42500.
80. Zhang T, Lu X, Beier F, et al., Rac1 activation induces tumour necrosis factor-α expression and cardiac dysfunction in endotoxemia. J Cell Mol Med 2011; 15: 1109-1121.
81. Worou ME, Belmokhtar K, Bonnet P, et al., Hemin decreases cardiac oxidative stress and fibrosis in a rat model of systemic hypertension via PI3K/Akt signalling. Cardiovasc Res 2011; 91: 320-329.
82. Ma J, Wang Y, Zheng D, et al., Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species-dependent and -independent pathways. Cardiovasc Res 2013; 97: 77-87.
83. Nagase M, Ayuzawa N, Kawarazaki W, et al., Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension 2012; 59: 500-506.
84. Heymes C, Bendall JK, Ratajczak P, et al., Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol 2003; 41: 2164-2171.
85. Krahn AD, Manfreda J, Tate RB, et al., The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995; 98: 476-484.
86. Carnes CA, Chung MK, Nakayama T, et al., Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 2001; 89: E32-38.
87. Shiroshita-Takeshita A, Schram G, Lavoie J, et al., Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation 2004; 110: 2313-2319.
88. Korantzopoulos P, Kolettis TM, Kountouris E, et al., Variation of inflammatory indexes after electrical cardioversion of persistent atrial fibrillation. Is there an association with early recurrence rates? Int J Clin Pract 2005; 59: 881-885.
89. Dudley SC, Jr., Hoch NE, McCann LA, et al., Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 2005; 112: 1266-1273.
90. Mihm MJ, Yu F, Carnes CA, et al., Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 2001; 104: 174-180.
91. Adam O, Frost G, Custodis F, et al., Role of Rac1 GTPase activation in atrial fibrillation. J Am Coll Cardiol 2007; 50: 359-367.
92. Adam O, Lavall D, Theobald K, et al., Rac1-induced connective tissue growth factor regulates connexin 43 and N-cadherin expression in atrial fibrillation. J Am Coll Cardiol 2010; 55: 469-480.
93. Reil JC, Hohl M, Oberhofer M, et al., Cardiac Rac1 overexpression in mice creates a substrate for atrial arrhythmias characterized by structural remodelling. Cardiovasc Res 2010; 87: 485-493.
94. Tsai CT, Lai LP, Kuo KT, et al., Angiotensin II activates signal transducer and activators of transcription 3 via Rac1 in atrial myocytes and fibroblasts: implication for the therapeutic effect of statin in atrial structural remodeling. Circulation 2008; 117: 344-355.
95. Dart RC, Sanders AB,. Oxygen free radicals and myocardial reperfusion injury. Ann Emerg Med 1988; 17: 53-58.
96. Ferrari R, Agnoletti L, Comini L, et al., Oxidative stress during myocardial ischaemia and heart failure. Eur Heart J 1998; 19 (suppl B): B2-11.
97. Kloner RA, Przyklenk K, Whittaker P,. Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues. Circulation 1989; 80: 1115-1127.
98. Khan M, Mohan IK, Kutala VK, et al., Cardioprotection by sulfaphenazole a cytochrome p450 inhibitor: mitigation of ischemia-reperfusion injury by scavenging of reactive oxygen species. J Pharmacol Exp Ther 2007; 323: 813-821.
99. Khan M, Brauner ME, Plewa MC, et al., Effect of pulmonary-generated reactive oxygen species on left-ventricular dysfunction associated with cardio-pulmonary ischemia-reperfusion injury. Cell Biochem Biophys 2011; In Press.
100. Fukui T, Yoshiyama M, Hanatani A, et al., Expression of p22-phox and gp91-phox, essential components of NADPH oxidase, increases after myocardial infarction. Biochem Biophys Res Commun 2001; 281: 1200-1206.
101. Krijnen PA, Meischl C, Hack CE, et al., Increased Nox2 expression in human cardiomyocytes after acute myocardial infarction. J Clin Pathol 2003; 56: 194-199.
102. Kim SY, Kwak JS, Shin JP, et al., The protection of the retina from ischemic injury by the free radical scavenger EGb 761 and zinc in the cat retina. Ophthalmologica 1998; 212: 268-274.
103. Ozaki M, Deshpande SS, Angkeow P, et al., Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo. FASEB J 2000; 14: 418-429.
104. Talukder MA, Elnakish MT, Yang F, et al., Cardiomyocyte-specific overexpression of an active form of Rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2013; 304: H294-302.
105. Madamanchi NR, Vendrov A, Runge MS,. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 29-38.
106. Ferri N, Contini A, Bernini SK, et al., Role of small GTPase protein Rac1 in cardiovascular diseases: development of new selective pharmacological inhibitors. J Cardiovasc Pharmacol 2013; In Press.
107. Nassar N, Cancelas J, Zheng J, et al., Structure-function based design of small molecule inhibitors targeting Rho family GTPases. Curr Top Med Chem 2006; 6: 1109-1116.
108. Sawada N, Li Y, Liao JK,. Novel aspects of the roles of Rac1 GTPase in the cardiovascular system. Curr Opin Pharmacol 2010; 10: 116-121.