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Diabetes 54:2882-2890, 2005
© 2005 by the American Diabetes Association, Inc.

Gene Delivery of Tim44 Reduces Mitochondrial Superoxide Production and Ameliorates Neointimal Proliferation of Injured Carotid Artery in Diabetic Rats

Takashi Matsuoka1, Jun Wada1, Izumi Hashimoto1, Yanling Zhang1, Jun Eguchi1, Norio Ogawa2, Kenichi Shikata1, Yashpal S. Kanwar3, and Hirofumi Makino1

1 Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
2 Department of Brain Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
3 Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois

Hyperglycemia induces the production of reactive oxygen species (ROS) from mitochondria, which is closely related to diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane (Tim)44 was identified by upregulation in streptozotocin (STZ)-induced diabetic mouse kidneys; Tim44 functions as a membrane anchor of mtHsp70 to TIM23 complex and is involved in the import of preproteins with mitochondria-targeted presequence into mitochondrial matrix. The process is dependent on inner membrane potential ({Delta}{psi}) and ATP hydrolysis on ATPase domain of mtHsp70. Here, we show that the gene delivery of Tim44 using pcDNA3.1 vector (pcDNA3.1/TIM44) into the balloon injury model of STZ-induced diabetic rats ameliorated neointimal proliferation. ROS production, inflammatory responses, and cell proliferation in injured carotid artery were diminished by delivery of pcDNA3.1/TIM44. In vitro experiments using human aortic smooth muscle cells (HASMCs) revealed that the gene delivery of Tim44 normalized high-glucose–induced enhanced ROS production and increased ATP production, alterations in inner membrane potential, and cell proliferation. Transfection of siRNA and pcDNA3.1/TIM44 using HASMC culture clarified that import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase was facilitated by Tim44. Tim44 and its related molecules in mitochondrial import machinery complex are novel targets in the therapeutic interventions for diabetes and its vascular complications.

Address correspondence and reprint requests to Jun Wada, MD, PHD, Assistant Professor, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail: junwada{at}md.okayama-u.ac.jp

Abbreviations: DMEM, Dulbecco’s modified Eagle’s medium; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; GFP, green fluorescent protein; HASMC, human aortic smooth muscle cell; HVJ, hemagglutination virus of Japan; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; Mn-SOD, manganese-containing SOD; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; SOD, superoxide dismutase; STZ, streptozotocin; TIM, translocase of inner mitochondrial membrane; TNF-{alpha}, tumor necrosis factor-{alpha}; UCP-1, uncoupling protein-1; VCAM-1, vascular cell adhesion molecule-1


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.