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J Thorac Cardiovasc Surg 2000;119:998-1007
© 2000 The American Association for Thoracic Surgery

Surgery For Acquired Cardiovascular Disease

Potential role of vacuolar H⁺–adenosine triphosphatase in neointimal formation in cultured human saphenous vein

From the Department of Thoracic and Cardiovascular Surgery,^a Kansai Medical University, Department of Surgery (II),^b School of Medicine, Kanazawa University, and the Laboratory of Biochemistry,^c Department of Molecular and Cell Biology, Faculty of Pharmaceutical Science, Kanazawa University, Kanazawa, Japan.

Address for reprints: 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 ).

Objective: Vacuolar H⁺–adenosine triphosphatase plays a pivotal role in pH regulation and molecular transport across the vacuolar membranes and is involved in cell proliferation and transformation. In the present study, possible involvement of vacuolar H⁺–adenosine triphosphatase in neointimal formation was investigated in an organ culture model of human saphenous vein.
Methods and results: Cultured saphenous vein segments developed neointimal formation and marked thickening of the media within 14 days. Neointimal formation and medial thickening were completely inhibited by 10 nmol/L bafilomycin A₁, a selective inhibitor of vacuolar H⁺-adenosine triphosphatase, although structurally related macrolide antibiotics FK-506 and erythromycin were without an effect. The neointimal cells were positive for -smooth muscle actin and vimentin but negative for desmin, indicative of myofibroblasts. The emergence of myofibroblasts was inhibited, and endothelial cells were preserved in the saphenous vein segments treated with bafilomycin A₁. Uptake of bromodeoxyuridine, a proliferation marker, by myofibroblasts was abrogated in the saphenous vein segments treated with 10 nmol/L bafilomycin A₁. Detection of apoptotic cells by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling concomitant with identification of desmin-expressing smooth muscle cells demonstrated that neointimal myofibroblasts, but not medial smooth muscle cells, that expressed desmin underwent apoptosis by treatment with bafilomycin A₁.
Conclusions: These results suggest that vacuolar H⁺–adenosine triphosphatase may be involved in myofibroblast growth that contributes to neointimal formation and medial thickening in cultured human saphenous vein. Increased sensitivity of myofibroblasts, but not endothelial cells, and differentiated smooth muscle cells to bafilomycin A₁ may have potential therapeutic implications in the treatment for vein graft disease.