| Project/Area Number |
22790734
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Jikei University School of Medicine |
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Principal Investigator |
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | 糖尿病性心筋症 / 12-リポキシゲナーゼ / 12-HETE / TNF-α / MCP-1 |
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| Research Abstract |
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. 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. 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 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 TNF-α by neonatal cardiomyocyte. Treatment with Cinnamy1-3, 4-dihydroxy-α-cyanocinnamate(CDC), a inhibitor of 12-LOX, decreased the expression of 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.
Cinnamy1-3, 4-dihydroxy-α-cyanocinnamate(CDC), a inhibitor of 12-LOX, decreased the expression of 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.
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