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CARDIOVASCULAR

Sepiapterin Decreases Acute Rejection and Apoptosis in Cardiac Transplants Independently of Changes in Nitric Oxide and Inducible Nitric-Oxide Synthase Dimerization

Transplant Surgery (G.M.P., I.A.I.), Orthopaedic Surgery (B.C.C.), Division of Cardiovascular Medicine (R.Q.M.), Department of Biophysics (J.W., J.V.-V.), Cardiovascular Research Center (G.M.P.), and Free Radical Research Center (G.M.P., J.V.-V.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland (A.K.K.)

Tetrahydrobiopterin (BH₄), a cofactor of inducible nitric-oxide synthase (iNOS), is an important post-translational regulator of NO bioactivity. We examined whether treatment of cardiac allograft recipients with sepiapterin [S-(-)-2-amino-7,8-dihydro-6-(2-hydroxy-1-oxopropyl)-4-(1H)-pteridinone], a precursor of BH₄, inhibited acute rejection and apoptosis in cardiac transplants. Heterotopic cardiac transplantation was performed in Wistar-Furth donor to Lewis recipient strain rats. Recipients were treated daily after transplantation with 10 mg/kg sepiapterin. Grafts were harvested on post-transplant day 6 for analysis of BH₄ (high-performance liquid chromatography), expression of inflammatory cytokines (reverse transcription- and real-time polymerase chain reaction), iNOS (Western blots), and NO (Griess reaction and NO analyzer). Histological rejection grade was scored, and graft function was determined by echocardiography. Apoptosis, protein nitration, and oxidative stress were determined by immunohistochemistry. Treatment of allografts with sepiapterin increased cardiac BH₄ levels by 3-fold without changing protein levels of GTP cyclohydrolase, the enzyme that regulates de novo BH₄ synthesis. Sepiapterin decreased inflammatory cell infiltrate and significantly inhibited histological rejection scores and apoptosis similar in magnitude to cyclosporine. Sepiapterin also decreased nitrative and oxidative stress. Sepiapterin caused a smaller increase in left ventricular mass versus untreated allografts but without improving fractional shortening. Sepiapterin did not alter tumor necrosis factor- and interferon- expression, whereas it decreased interleukin (IL)-2 expression. Sepiapterin did not change total iNOS protein or monomer levels, or plasma and tissue NO metabolites levels. It is concluded that the mechanism(s) of antirejection are due in part to decreased apoptosis, protein nitration, and oxidation of cardiomyocytes, which seems to be mediated at the immune level by limiting inflammatory cell infiltration via decreased IL-2-mediated T-lymphocyte expansion.

Address correspondence to: Dr. Galen M. Pieper, Division of Transplant Surgery, Medical College of Wisconsin, 9200 West Wisconsin Ave., Milwaukee, WI 53226. E-mail: gmpieper{at}mcw.edu