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(Circulation Research. 2002;91:1135.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Apoptosis and Cellular Activation in the Pathogenesis of Acute Vascular Rejection

Zoie E. Holzknecht, Karisha L. Kuypers, Timothy B. Plummer, Josie Williams, Matilda Bustos, Gregory J. Gores, Gregory J. Brunn, Jeffrey L. Platt

From the Departments of Surgery (Z.E.H., K.L.K., T.B.P., J.W., G.J.B., J.L.P.), Gastroenterology (G.J.G.), Pediatrics (J.L.P.), and Immunology (J.L.P.), Mayo Clinic, Rochester, Minn, and the Division of Hepatology and Gene Therapy (M.B.), Universidad de Navarra, Pamplona, Spain.

Correspondence to Jeffrey L. Platt, MD, Transplantation Biology, Medical Sciences Building, Room 2-66, Mayo Clinic, 200 First St Southwest, Rochester, MN 55905. E-mail platt.jeffrey{at}mayo.edu

Acute vascular or humoral rejection, a vexing outcome of organ transplantation, has been attributed by some to activation and by others to apoptosis of endothelial cells in the graft. We asked which of these processes causes acute vascular rejection by tracing the processes during the development of acute vascular rejection in porcine cardiac xenografts performed in baboons. Apoptosis, assayed by terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL), expression of activated caspase-3, and proapoptotic genes Bax and Bcl-x_L, was not detected until acute vascular rejection was well advanced, and even then, apoptosis was largely confined to myocytes. Activation of the endothelium, as evidenced by expansion of rough endoplasmic reticulum and increased ribosomal antigen and phospho-p70 S6 kinase, occurred early in the course of acute vascular rejection and progressed through the disease process. These findings suggest that acute vascular rejection is caused by an active metabolic process and not by apoptosis in the endothelium.

Key Words: apoptosis • endothelial cells • xenotransplantation • cardiac transplantation

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