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(Circulation. 2008;118:S58-S64.)
© 2008 American Heart Association, Inc.

Myocardial Protection, Perioperative Management, and Vascular Biology

Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

Rohit Sheshgiri, BSc; Vivek Rao, MD, PhD; Laura C. Tumiati, BSc; Rong Xiao, BSc; Jessica L. Prodger, BSc; Mitesh Badiwala, MD; Clifford Librach, MD; Diego H. Delgado, MD, MSc

From the Heart Transplant Program (R.S., V.R., L.C.T., J.L.P., M.B., D.H.D.), Peter Munk Cardiac Center, Toronto General Hospital, University Health Network, Toronto, Canada; the Institute of Medical Science (R.S., V.R., J.L.P., M.B.), Faculty of Medicine, University of Toronto, Toronto, Canada; and the Department of Obstetrics and Gynecology (R.X., C.L.), Sunnybrook and Women’s College Health Sciences Centre, Toronto, Canada.

Correspondence to Diego H. Delgado, MD, MSc, NCSB 11C-1201, Toronto General Hospital, 585 University Avenue, Toronto, Ontario, Canada, M5G 2N2. E-mail diego.delgado{at}uhn.on.ca

Background— Human leukocyte antigen-G (HLA-G) expression in heart transplant patients has been negatively associated with acute cellular rejection and cardiac allograft vasculopathy. We assessed HLA-G expression in vascular human endothelial and smooth muscle cell cultures to determine if future therapeutic agents can be targeted toward inducing HLA-G expression to protect against allograft rejection and vasculopathy.

Methods and Results— Human coronary artery endothelial, aortic endothelial, and coronary artery smooth muscle cell cultures were exposed to cytokines (interferon- or interleukin-10), hypoxia/reoxygenation stress, immunosuppressive agents (cyclosporine, sirolimus, or tacrolimus), or progesterone. HLA-G was not expressed by untreated, normoxic cells. Furthermore, maximal doses of interferon-, interleukin-10, cyclosporine, sirolimus, or tacrolimus, as well as exposure to hypoxia/reoxygenation, failed to induce HLA-G expression. HLA-G, which has previously not been detected in adult vascular endothelial and smooth muscle cells, was detected by enzyme-linked immunosorbent assay and flow cytometry in human coronary artery endothelial, human coronary aortic endothelial, and human coronary artery smooth muscle cultures after incubation with progesterone in a dose-dependent manner (P<0.001) with no change in cellular proliferation ability or viability. This effect was partially blocked in the presence of mifepristone, a progesterone receptor antagonist (human coronary artery endothelial: 48.8±15.6%; human coronary aortic endothelial: 59.5±9.5%; human coronary artery smooth muscle: 59.8±9.8% of control; P<0.05). Progesterone-induced HLA-G expression was not protective against hypoxia/reoxygenation injury.

Conclusions— HLA-G is not expressed at baseline in vascular endothelial and smooth muscle cells but can be induced by exposure to progesterone. Although tightly regulated, induction of HLA-G expression in these cells may represent a promising and novel therapeutic strategy to protect against rejection and cardiac allograft vasculopathy after heart transplantation.

Key Words: endothelium • HLA-G • progesterone • rejection • transplantation