Is mycophenolate more than just an immunosuppressant?--An overview.
The development of immunosuppressant compounds, such as cyclosporine and tacrolimus was crucial to the success of transplant surgery and for treatment of autoimmune diseases. However, immunosuppressant therapy may increase the concentrations of reactive oxygen species (ROS), inducing oxidative damage such as an increased vascular damage. The major source of ROS in the vascular endothelial cells is NADPH oxidase. The subunit structure and function of this enzyme complex in vascular cells differs from that in phagocytic leucocytes. The enzyme subunits Nox1, Nox2 and Nox4 are only found in vascular cells. The GTP-dependent protein subunit Rac 1 needs to be activated for this enzyme to function. Inhibiting this protein subunit should reduce NADPH oxidase-induced oxidative stress. In the cardiovascular system, oxidative stress is observed as hypertension, hypertrophy, fibrosis, conduction abnormalities and endothelial dysfunction, as well as cardiac allograft vasculopathy in transplant patients. In contrast to cyclosporine and tacrolimus, the immunosuppressant mycophenolate inhibits the Rac 1 subunit thus inhibiting NADPH oxidase in the vasculature. This may reduce oxidative stress, prevent the development of cardiac allograft vasculopathy, decrease the deterioration of vascular function and improve cardiovascular function chronically in transplant patients. This overview discusses whether this antioxidant immunosuppressive property could translate into a more general protective role for mycophenolate in the prevention of cardiovascular disease.
Iyer
Abishek
A
School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia.
Brown
Lindsay
L
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology / Q000637:transplantation; D065095:Calcineurin Inhibitors; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000975:Antioxidants; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D016572:Cyclosporine; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D009173:Mycophenolic Acid; D016559:Tacrolimus