Abstract 8230: Arachidonic 12-lipoxygenase-induced Inflammation Promotes The Development Of Diabetic Cardiomyopathy
Diabetic mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood, but precise mechanism underlying diabetic cardiomyopathy is still unknown. To investigate the molecular mechanisms of diabetic cardiomyopathy, we created a diabetic cardiomyopathy model (streptozotocin (STZ) injection rat) and performed microarray analysis. Echocardiography showed that STZ injection rat developed diastolic and systolic dysfunction and cardiac fibrosis was increased in STZ injection rat. Among the genes analyzed, arachidonic 12-lipoxygenase (12-LOX) was upregulated in the heart of STZ rat. Northern blotting and ELISA analysis demonstrated that mRNA level of 12-LOX and production of 12(s)-HETE, a major metabolite of 12-LOX, were upregulated in the heart of STZ rat compared to those of control rat heart. Until recently, 12-LOX has been reported to play an important role in the development of atherogenesis, diabetes, and neurogenerative disease. However, the role of 12-LOX in diabetic cardiomyopathy has not been examined. To determine the role of 12-LOX in STZ injection heart, we created STZ injection mice (WT-STZ) and compared to those of 12-LOX KO (KO-STZ) mice. Disruption of 12-LOX significantly reduced cardiac fibrosis and improving diastolic and systolic dysfunction. Moreover the expression of inflammatory cytokine genes such as MCP-1 and TNF-α and STZ-induced reactive oxygen species were significantly inhibited by disruption of 12-LOX. In vitro experiment reveal that hyperglycemia induced expression of 12-LOX as well as MCP-1 and TNF-α by neonatal cardiomyocyte. Treatment with Cinnamy1-3,4-dihydroxy-α-cyanocinnamate (CDC) , a inhibitor of 12-LOX, decreased the expression of MCP-1 and TNF-α by cardiomyocyte under high glucose stimulation. Our results suggest that cardiac 12-LOX-induced inflammation is involved in the development of diabetic cardiomyopathy and that inhibition of 12-LOX could be a novel treatment for this condition.
- © 2011 by American Heart Association, Inc.