title: Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy.
abstract: Diabetes affects cardiac structure and function, and it has been suggested that diabetes leads to cardiomyopathy. Arachidonate 12/15-lipoxygenase (LOX) has been suggested to play an important role in atherogenesis and heart failure. However, the role of 12/15-LOX in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac 12/15-LOX on diabetic cardiomyopathy. We created streptozotocin (STZ)-induced diabetic mice and compared them with Alox15-deficient mice. Expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB were upregulated in STZ-induced diabetic hearts. Disruption of 12/15-LOX significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of 12/15-LOX inhibited the increases of TNF-α and NF-κB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevented STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induced the expression of 12/15-LOX as well as TNF-α, NF-κB, and collagen markers. These increases were inhibited by treatment of the 12/15-LOX inhibitor. Our results suggest that cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy and that inhibition of 12/15-LOX could be a novel treatment for this condition.
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan kayama@jikei.ac.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kayama
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sakamoto
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Iuchi
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Katoh
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nagoshi
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Tojo
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan PRESTO, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshimura
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Utsunomiya
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D058065:Diabetic Cardiomyopathies / Q000209:etiology* / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology; D015971:Gene Expression Regulation, Enzymologic; D006943:Hyperglycemia / Q000150:complications; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase