Published online before print November 13, 2006, doi: 10.1161/01.HYP.0000251161.93696.d0
(Hypertension. 2007;49:25.)
© 2007 American Heart Association, Inc.
Editorial Commentaries |
Mycophenolic Acid Is a New Nox2 Inhibitor
From the Division of Cardiology, Emory University, Atlanta, Ga.
Correspondence to Kathy Griendling, Emory University, Division of Cardiology, 1639 Pierce Dr, WMB 319, Atlanta, GA 30322. E-mail kgriend@emory.edu
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
Organ transplantation owes its spectacular development in recent decades to the introduction of immunosuppressive drugs capable of preventing allograft rejection. However, vasculopathy remains a major cause of long-term graft failure; thus, a better understanding of its mechanisms is required to improve tolerance. Because endothelial dysfunction is an early manifestation of vascular disorders, Krötz et al,1 in this issue of Hypertension, hypothesized that endothelial cells (ECs) may be directly affected by immunosuppressive treatment. Therefore, they tested 3 major classes of these drugs with distinct mechanisms of action and effects on the vasculature.
The first group includes cyclosporine A (CsA) and FK506 (tacrolimus). These are inhibitors of calcineurin, a ubiquitous calcium-dependent serine and threonine phosphatase (or PP2B). Calcineurin activates transcription factors of the nuclear factor of activated T cells family responsible for expression of surface receptors, cytokines, and chemokines in lymphocytes.2 Calcineurin inhibitors thus induce immunosuppression by blocking lymphocyte proliferation. However, adverse effects include nephrotoxicity, hyperlipidemia, endothelial dysfunction, and hypertension. In the endothelium, calcineurin inhibitors can increase endothelin-1 release,2 prevent dephosphorylation and activation of endothelial nitric oxide synthase (eNOS),3 and increase superoxide production.4
The second type of drug used by Krötz et al1 is mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase, the rate-limiting enzyme in de novo guanosine synthesis. Lymphocytes depend on this enzyme, in contrast to most other cells, including ECs, which can also use an alternative salvage pathway for guanosine synthesis. Furthermore, whereas resting lymphocytes and other cell types express one type of inosine monophosphate dehydrogenase, activated
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