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

MATSUOKA, Takashi ; WADA, Jun ; HASHIMOTO, Izumi ; YANLING ZHANG ; EGUCHI, Jun ; OGAWA, Norio ; SHIKATA, Kenichi ; KANWAR, Yashpal S ; MAKINO, Hirofumi

Diabetes (New York, N.Y.), 2005-10, Vol.54 (10), p.2882-2890 [Periódico revisado por pares]

Alexandria, VA: American Diabetes Association

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Gene Delivery of Tim44 Reduces Mitochondrial Superoxide Production and Ameliorates Neointimal Proliferation of Injured Carotid Artery in Diabetic Rats
Autor: MATSUOKA, Takashi ; WADA, Jun ; HASHIMOTO, Izumi ; YANLING ZHANG ; EGUCHI, Jun ; OGAWA, Norio ; SHIKATA, Kenichi ; KANWAR, Yashpal S ; MAKINO, Hirofumi
Assuntos: Adenosine Triphosphate - metabolism ; Animals ; Aorta ; Biological and medical sciences ; Care and treatment ; Carotid artery diseases ; Carotid Artery Injuries - pathology ; Carrier Proteins - genetics ; Catheterization ; Cell Division ; Cells, Cultured ; Cytokines - genetics ; Diabetes ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Experimental - pathology ; Diabetes research ; Diabetes. Impaired glucose tolerance ; Diagnosis ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Gene Expression ; Genetic Vectors ; Glucose - pharmacology ; Glutathione Reductase - metabolism ; Humans ; Hyperplasia ; Male ; Medical sciences ; Membrane Potentials ; Membrane Proteins - genetics ; Mitochondria - metabolism ; Mitochondrial Proteins - genetics ; Muscle, Smooth, Vascular - metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species - metabolism ; Risk factors ; RNA, Small Interfering - genetics ; Superoxide Dismutase - metabolism ; Superoxides - metabolism ; Transfection ; Tunica Intima - pathology ; Vascular Cell Adhesion Molecule-1 - genetics
É parte de: Diabetes (New York, N.Y.), 2005-10, Vol.54 (10), p.2882-2890
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: Gene Delivery of Tim44 Reduces Mitochondrial Superoxide Production and Ameliorates Neointimal Proliferation of Injured Carotid Artery in Diabetic Rats Takashi Matsuoka 1 , Jun Wada 1 , Izumi Hashimoto 1 , Yanling Zhang 1 , Jun Eguchi 1 , Norio Ogawa 2 , Kenichi Shikata 1 , Yashpal S. Kanwar 3 and Hirofumi Makino 1 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 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 Abstract 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 (Δψ) 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. 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-α, tumor necrosis factor-α UCP-1, uncoupling protein-1 VCAM-1, vascular cell adhesion molecule-1 Footnotes Accepted July 6, 2005. Received March 20, 2005. DIABETES
Editor: Alexandria, VA: American Diabetes Association
Idioma: Inglês

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

MATSUOKA, Takashi ; WADA, Jun ; HASHIMOTO, Izumi ; YANLING ZHANG ; EGUCHI, Jun ; OGAWA, Norio ; SHIKATA, Kenichi ; KANWAR, Yashpal S ; MAKINO, Hirofumi

Alexandria, VA: American Diabetes Association

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