Arachidonate 12/15-Lipoxygenase–Induced Inflammation and Oxidative Stress Are Involved in the Development of Diabetic Cardiomyopathy

• DOI: 10.2337/db13-1896
• Publication Date: 2014-09-04T14:16:25Z
• Authors: Hirofumi Suzuki; Yosuke Kayama; Masaya Sakamoto; Hiroyuki Iuchi; Ippei Shimizu; Takuya Yoshino; Daisuke Katoh; Tomohisa Nagoshi; Katsuyoshi Tojo; Tohru Minamino; Michihiro Yoshimura; Kazunori Utsunomiya
• Keywords: Blood Glucose; Inflammation; Mice, Knockout; 0301 basic medicine; Diabetic Cardiomyopathies; Arachidonate 12-Lipoxygenase; Fibrosis; Gene Expression Regulation, Enzymologic; Diabetes Mellitus, Experimental; Up-Regulation; 3. Good health; Mice; Oxidative Stress; 03 medical and health sciences; Hyperglycemia; Animals; Arachidonate 15-Lipoxygenase

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.