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(Circulation. 2000;102:III-269.)
© 2000 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Vacuolar H⁺-ATPase Plays a Crucial Role in Growth and Phenotypic Modulation of Myofibroblasts in Cultured Human Saphenous Vein

Hajime Otani, MD; Tadashi Yamamura, MD; Yoshihisa Nakao, MD; Reiji Hattori, MD; Hirohumi Fujii, MD; Hideki Ninomiya, MD; Masakuni Kido, MD; Hideki Kawaguchi, MD; Motohiko Osako, MD; Hiroji Imamura, MD; Tetsuo Ohta, MD; Shoji Ohkuma, PhD

From the Department of Thoracic and Cardiovascular Surgery (H.O., T.Y., Y.N., R.H., H.F., H.N., M.K., H.K., M.O., H.I.), Kansai Medical University, Moriguchi, Japan; and Department of Surgery (II) (T.O.), and Laboratory of Biochemistry (S.O.), Department of Molecular and Cell Biology, Faculty of Pharmaceutical Science, Kanazawa University, Kanazawa, Japan.

Correspondence to Hajime Otani, MD, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570, Japan. E-mail otanih{at}takii.kmu.ac.jp

Background—The molecular mechanism of neointimal hyperplasia after vein graft surgery remains elusive. Vacuolar H⁺-ATPase (V-ATPase) is involved in intracellular trafficking and may play a crucial role in neointimal cell growth.

Methods and Results—Cultured human saphenous vein segments developed neointimal formation within 10 days. Neointimal cells were positive for vimentin and -smooth muscle actin but negative for desmin, which is indicative of myofibroblasts. Those myofibroblasts were found to have originated from periadventitial fibroblasts, which upregulated the expression of 16-kDa proteolipid of V-ATPase before proliferation and phenotypic modulation. Neointimal myofibroblast growth and survival were highly sensitive to inhibition of V-ATPase by bafilomycin A₁ (BA₁), because the incorporation of [³H]thymidine into the myofibroblasts was significantly inhibited by nanomolar concentrations of BA₁ and apoptotic cell death was induced by a similar concentration range of BA₁. In contrast, endothelial cells and differentiated smooth muscle cells were resistant to apoptosis by BA₁.

Conclusions—These results suggest that V-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts that contributes to neointimal formation in cultured human saphenous vein.

Key Words: vacuolar H⁺-ATPase • myofibroblasts • neointima • apoptosis • veins