Inhibition of CTRP9, a novel and cardiac-abundantly expressed cell survival molecule, by TNFα-initiated oxidative signaling contributes to exacerbated cardiac injury in diabetic mice

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• 作者：Hui Su (1) (2)
  Yuexing Yuan (1)
  Xiao-Ming Wang (2)
  Wayne Bond Lau (1)
  Yajing Wang (1)
  Xiaoliang Wang (1)
  Erhe Gao (3)
  Walter J. Koch (3)
  Xin-Liang Ma (1) (4)
  
• 关键词：Oxidative stress ; Diabetes ; Cytokines ; Myocardial ischemia
• 刊名：Basic Research in Cardiology
• 出版年：2013
• 出版时间：January 2013
• 年：2013
• 卷：108
• 期：1
• 全文大小：587KB
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• 作者单位：Hui Su (1) (2)
  Yuexing Yuan (1)
  Xiao-Ming Wang (2)
  Wayne Bond Lau (1)
  Yajing Wang (1)
  Xiaoliang Wang (1)
  Erhe Gao (3)
  Walter J. Koch (3)
  Xin-Liang Ma (1) (4)
  
  1. Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA, 19107, USA
  2. Department of Geriatrics, Xijing Hospital, the Fourth Military Medical University, 127 West Changle Rd, Xi’an, 710032, China
  3. Center for Translational Medicine, Temple University School of Medicine, 3500?N Broad St, Philadelphia, PA, 19140, USA
  4. Department of Emergency Medicine, 1020 Sansom Street, 239 Thompson Building, Philadelphia, PA, 19107, USA
  
• ISSN：1435-1803

文摘

Recently identified as adiponectin (APN) paralogs, C1q/TNF-related proteins (CTRPs) share similar metabolic regulatory functions as APN. The current study determined cardiac expression of CTRPs, their potential cardioprotective function, and investigated whether and how diabetes may regulate cardiac CTRP expression. Several CTRPs are expressed in the heart at levels significantly greater than APN. Most notably, cardiac expression of CTRP9, the closest paralog of APN, exceeds APN by >100-fold. Cardiac CTRP9 expression was significantly reduced in high-fat diet-induced diabetic mice. In H9c2 cells, tumor necrosis factor-alpha (TNF-α) strongly inhibited CTRP9 expression (>60?%), and significantly reduced peroxisome proliferator activated receptor-gamma (PPARγ), a known transcription factor promoting adiponectin expression. The inhibitory effect of TNF-α on PPARγ and CTRP9 was reversed by Tiron or rosiglitazone. CTRP9 knockdown significantly enhanced, whereas CTRP9 overexpression significantly attenuated simulated ischemia/reperfusion injury in H9c2 cells. In vivo CTRP9 administration to diabetic mice significantly attenuated NADPH oxidase expression and superoxide generation, reduced infarct size, and improved cardiac function. To the best of our knowledge, this is the first study providing evidence that downregulation of CTRP9, an abundantly expressed and novel cell survival molecule in the heart, by TNF-α-initiated oxidative PPARγ suppression contributes to exacerbated diabetic cardiac injury. Preservation of CTRP9 expression or augmentation of CTRP9-initiated signaling mechanisms may be the potential avenues for ameliorating ischemic diabetic cardiac injury.