OJOTS  Vol.3 No.2 , May 2013
Role of Oxidative Stress in Cardiac Allograft Vasculopathy
Abstract: Cardiac Allograft Vasculopathy, an accelerated form of arterial occlusive disease, is the major cause of death in the long-term after heart transplantation. Multiple factors influence the initiation and progression of CAV. These include ischemia-reperfusion, dyslipidemia, insulin resistance, and hypertension due to the use of immunosuppressive agents, the direct effects of immunosuppressive agents on endothelial function, and viruses (CMV). Impaired endothelial function reflects abnormalities in the production or activity of several vasoactive substances. Disruption of the nitric oxide synthase (NOS) pathway leads to changes in vascular reactivity, structure, and interaction with circulating blood components. Since endothelium-derived nitric oxide (NO) suppresses vascular cell proliferation and vascular inflammation, a deficit in vascular NO facilitates development of CAV. The link between oxidative stress and CAV largely exists in the balance between free radical superoxide generation and NO production. This review focuses on identifying the oxidative stress factors affecting CAV.
Cite this paper: Nair, N. , Gongora, E. and Reynolds, J. (2013) Role of Oxidative Stress in Cardiac Allograft Vasculopathy. Open Journal of Organ Transplant Surgery, 3, 36-41. doi: 10.4236/ojots.2013.32007.

[1]   J. D. Hosenpud, L. E. Benell, B. M. Keck, B. Fiol, M. M. Boucek and R. J. Novick, “The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Report,” The Journal of Heart and Lung Transplantion, Vol. 18, No. 7, 1999, pp. 611-626. doi:10.1016/S1053-2498(99)00037-6

[2]   P. Vallance, A. Leone, A. Calver, J. Collier and S. Moncada, “Endogenous Dimethlarginine as an Inhibitor of Nitric Oxide Synthesis,” Journal of Cardiovascular Phar- macology, Vol. 20, Suppl. 12, 1992, pp. S60-S62. doi:10.1097/00005344-199204002-00018

[3]   M. E. Russell, “Cardiac Allograft Vasculopathy—A Changing Perspective,” Zeitschrift für Kardiologie, Vol. 89, Suppl. 9, 2000, pp. 6-10.

[4]   M. T. Grattan, C. E. Moreno-Cabral, V. A. Starnes, P. E. Oyer, E. B. Stinson and N. E. Shumway. “Cytomegalovirus Infection Is Associated with Cardiac Allograft Rejection and Atherosclerosis,” Journal of the American Medical Association, Vol. 261, No. 42, 1989, pp. 3561- 3566. doi:10.1001/jama.1989.03420240075030

[5]   M. C. van Dam-Mieras, A. D. Muller, V. W. van Hinsbergh, W. J. Mullers, P. H. Bomans and C. A. Bruggeman, “The Procoagulant Response of Cytomegalovirus Infected Endothelial Cells,” Thrombosis and Haemostasis, Vol. 68, No. 3, 1992, pp. 364-370.

[6]   M. Billstrom Schroeder and G. S. Worthen, “Viral Regulation of RANTES Expression During Human Cytomegalovirus Infection of Endothelial Cells,” Journal of Virology, Vol. 75, No. 7, 2001, pp. 3383-3390. doi:10.1128/JVI.75.7.3383-3390.2001

[7]   M. E. Billingham, “Histopathology of Graft Coronary Disease,” Journal of Heart and Lung Transplantation, Vol. 11, No. 3, 1992, pp.S38-S44.

[8]   M. Weis and W. VonScheidt, “Coronary Atherosclerosis in the Transplanted Heart,” Annual Review of Medicine, Vol. 51, 2000, pp. 81-100. doi:10.1146/

[9]   M, Weis, S. Pehlivali and W. von Scheidt, “Heart Allograft Endothelial Cell Dysfunction. Cause, Course, and Consequences,” Zeitschrift für Kardiologie, Vol. 89, Suppl. 9, 2000, pp. 58-62.

[10]   W. F. Fearon, M. Nakamura, D. P. Lee, et al., “Simultaneous Assessment of Fractional and Coronary Flow Reserves in Cardiac Transplant Recipients: Physiologic Investigation for Transplant Arteriopathy (PITA Study),” Circulation, Vol. 108, No, 2003, pp. 1605-1610. doi:10.1161/01.CIR.0000091116.84926.6F

[11]   M. Weis, W. P. Wolf, N. Mazilli, et al., “Variations of Segmental Endothelium-Dependent and Endothelium-Independent Vasomotor Tone after Cardiac Transplantation (Qualitative Changes in Endothelial Function),” American Heart Journal, Vol. 134 No. 2, 1997, pp. 306- 315. doi:10.1016/S0002-8703(97)70139-X

[12]   C. B. Treasure, J. A. Vita, P. Ganz, et al., “Loss of the Coronary Microvascular Response to Acetylcholine in Cardiac Transplant Patients,” Circulation, Vol. 86, No. 4, 1992, pp. 1156-1164. doi:10.1161/01.CIR.86.4.1156

[13]   J. Koglin, D. J. Granville, T. Glysing-Jensen, J. S. Mudgett, C. M. Carthy, B. M. McManus and M. E. Russell, “Attenuated Acute Cardiac Rejection in NOS2?/? Recipients Correlates with Reduced Apoptosis,” Circulation, Vol. 99, No. 1999, pp. 836-842. doi:10.1161/01.CIR.99.6.836

[14]   M. E. Russell, A. F. Wallace, L. R. Wyner, J. B. Newell and M. J. Karnovsky, “Upregulation and Modulation of Inducible Nitric Oxide Synthase in Rat Cardiac Allografts with Chronic Rejection and Transplant Arteriosclerosis,” Circulation. Vol. 92, No. 3, 1995, pp. 457-464. doi:10.1161/01.CIR.92.3.457

[15]   N. K. Worrall, W. D. Lazenby, T. P. Misko, et al., “Modulation of in Vivo Alloreactivity by Inhibition of Inducible Nitric Oxide Synthase,” The Journal of Experimental Medicine, Vol. 181, No. 1, 1995, pp. 63-70. doi:10.1084/jem.181.1.63

[16]   E. Akizuki, T. Akaike, S. Okamoto, et al., “Role of Nitric Oxide and Superoxide in Acute Cardiac Allograft Rejection in Rats,” Proceeding of the Society of Experimental Biology and Medicine, Vol. 225, No. 2, 2000, pp. 151-159. doi:10.1046/j.1525-1373.2000.22519.x

[17]   G. Hall, J. D. Hasday and T. B. Rogers, “Regulating the Regulator: NF-KappaB Signaling in Heart,” Journal of Molecular and Cellular Cardiology, Vol. 41, No. 4, 2006, pp. 580-591. doi:10.1016/j.yjmcc.2006.07.006

[18]   T. Hasegawa, K. Iwanaga, D. E. Hultquist, H. Liao, S. H. Visovatti and D. J. Pinsky. “Suppression of Nitrosative and Oxidative Stress to Reduce Cardiac Allograft Vasculopathy,” American Journal of Physiology Heart and Circulatory Physiology, Vol. 296, No. 4, 2009, pp. H1007-H1016. doi:10.1152/ajpheart.00498.2008

[19]   A. Iyer and L. Brown, “Is Mycophenolate More than Just an Immunosuppressant? An Overview,” Indian Journal of Biochemisty and Biophysics, Vol. 46, No. 1, 2009, pp. 25-30.

[20]   J. Najbauer, B. A. Johnson, A. L. Young and D. W. Aswad, “Peptides with Sequences Similar to Glycine, Arginine-Rich Motifs in Proteins Interacting with RNA Are Efficiently Recognized by Methyltransferase(s) Modifying Arginine in Numerous Proteins,” The Journal of Biological Chemistry, Vol. 268, No. 14, 1993, pp. 10501-10509.

[21]   S. Bode-Boger, R. H. Boger, S. Kienke, Junker and J. C. Frolich, “Elevated L-Arginine/Dimethylarginine Ratio Contributes to Enhanced Systemic NO Production by Dietary L-Arginine in Hypercholesterolemic Rabbits,” Biochemical and Biophysical Research Communications, Vol. 219, No. 1996, pp. 598-603. doi.10.1006/bbrc.1996.0279

[22]   J. Cooke and V. Dzau, “Derangements of the Nitric Oxide Synthase Pathway, L-Arginine, and Cardiovascular Disease,” Circulation, Vol. 96, No. 2, 1997, pp. 379-382.

[23]   H. Drexler, T. A. Fischell, F. J. Pinto, et al., “Effect of L-arginine on Coronary Endothelial Function in Cardiac Transplant Recipients: Relation to Vessel Wall Morphology,” Circulation. Vol. 89, No. 4, 1994, pp.1615-1623. doi:10.1161/01.ATV.14.5.753

[24]   A. J. Cayatte, J. J. Palacino, K. Horten and R. A. Cohen, “Chronic Inhibition of Nitric Oxide Production Accelerates Neointima Formation and Impairs Endothelial Function in Hypercholesterolemic Rabbits,” Arteriosclerosis and Thrombosis, Vol. 14, No. 5, 1994, pp. 753-759. doi:10.1161/01.ATV.14.5.753

[25]   P. L. Huang, “Disruption of the Endothelial Nitric Oxide Synthase Gene: Effect on Vascular Response to Injury,” The American Journal of Cardiology, Vol. 82, No. 10A, 1998, pp. 57S-59S. doi:10.1016/S0002-9149(98)00679-1

[26]   J. Cooke, A. Singer, P. Tsao, P. Zera, R. A. Rowan and M. E. Billingham, “Anti-Atherogeneic Effects of L-Arginine in the Hypercholesterolemic Rabbit,” The Journal of Clinical Investigation, Vol. 90, No. 3, 1992, pp. 1168- 1172. doi:10.1172/JCI115937

[27]   H. E. von der Leyen, G. H. Gibbons, R. Morishita, et al., “Gene Therapy Inhibiting Neointimal Vascular Lesion: In Vivo Transfer of Endothelial Cell Nitric Oxide Synthase Gene,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 4, 1995, pp. 1137-1141. doi:10.1073/pnas.92.4.1137

[28]   H. Dayoub, V. Achan, S. Adimoolam, et al., “Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis: Genetic and Physiological Evidence,” Circulation, Vol. 108, No. 24, 2003, 2042-3047. doi:10.1161/01.CIR.0000101924.04515.2E

[29]   M. Tanaka, K. Sydow, F. Gunawan, et al., “Dimethylarginine Dimethylaminohydrolase Overexpression Suppresses Graft Coronary Artery Disease in Murine Cardiac Allografts,” Circulation, Vol. 112, No. 11, 2005, pp. 1549-1556. doi:10.1161/CIRCULATIONAHA.105.537670

[30]   A. Ito, P. S. Tsao, S. Adimoolam, M. Kimoto, T. Ogawa and J. P. Cooke, “Novel Mechanism for Endothelial Dysfunction: Dysregulation of Dimethylarginine Dimethylaminohydrolase,” Circulation, Vol. 99, No. 24, 1999, pp. 3092-3095. doi:10.1161/01.CIR.99.24.3092

[31]   M. Weis, T. N. Kledal, K.Y. Lin, et al., “Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway: Role of Asymmetric Dimethylarginine in Transplant Arteriosclerosis,” Circulation, Vol. 109, No. 4, 2004, pp. 500-505. doi:10.1161/01.CIR.0000109692.16004.AF

[32]   L. Potena, W. F. Fearon, K. Sydow, et al., “Asymmetric Dimethylarginine and Cardiac Allograft Vasculopathy Progression: Modulation by Sirolimus,” Transplantation, Vol. 85, No. 6, 2008, pp. 827-833. doi:10.1097/TP.0b013e318166a3a4

[33]   K. Nishio, M. Sakurai, T. Kusuyama, et al., “A Randomized Comparison of Pioglitazone to Inhibit Restenosis after Coronary Stenting in Patients with Type 2 Diabetes,” Diabetes Care, Vol. 29, No. 1, 2006, pp. 101-106. doi:10.2337/diacare.29.01.06.dc05-1170

[34]   N. Marx, J. Wohrle, T. Nusser, et al., “Pioglitazone Reduces Neointima Volume after Coronary Stent Implantation: A Randomized, Placebo-Controlled, Double-Blind Trial in Nondiabetic Patients,” Circulation, Vol. 112, No. 18, 2005, pp. 2792-2798. doi:10.1161/CIRCULATIONAHA.105.535484

[35]   J. M. Sánchez-Gómez, L. Martínez-Dolz, I. Sánchez-Lázaro, et al., “Influence of Metabolic Syndrome on Development of Cardiac Allograft Vasculopathy in the Transplanted Heart,” Transplantation, Vol. 93, No. 1, 2012, pp. 106-111. doi:10.1097/TP.0b013e3182398058

[36]   O. Biadi, L. Potena, W. F. Fearon, et al., “Interplay between Systemic Inflammation and Markers of Insulin Resistance in Cardiovascular Prognosis after Heart Transplantation,” The Journal of Heart and Lung Transplantation, Vol. 26, No. 4, 2007, pp. 324-330. doi:10.1016/j.healun.2007.01.020

[37]   T. Hasegawa ,K. Okada, Y. Okita and D. J. Pinsky, “Antioxidant Properties of Pioglitazone Limit Nicotinamide Adenine Dinucleotide Phosphate Hydrogen Oxidase and Augment Superoxide Dismutase Activity in Cardiac Allotransplantation,” The Journal of Heart and Lung Transplantation, Vol. 30, No. 10, 2011, pp. 1186-1196. doi:10.1016/j.healun.2011.07.006

[38]   R. Tuuminen, S. Syrj?l?, R. Krebs, et al., “Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection through Microvascular Protection,” Circulation, Vol. 124, No. 10, 2011, pp. 1138-1150. doi:10.1161/CIRCULATIONAHA.110.005249

[39]   F. Hua, T. Ha, J. Ma, et al., “Protection Against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice is Mediated through a Phosphoinositide 3-Kinase-De- pendent Mechanism,” Journal of Immunology, Vol. 178, No. 11, 2007, pp. 7317-7324.

[40]   Y. Sakata, J. W. Dong, J. G. Vallejo, et al., “Toll-Like Receptor 2 Modulates Left Ventricular Function Following Ischemia-Reperfusion Injury,” American Journal of Physiology. Heart and Circulatory Physiology, Vol. 292, No. 1, 2007, pp. H503-H509. doi:10.1152/ajpheart.00642.2006