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• Research Paper Volume 12, Issue 6 pp 5411-5422

  HDAC6 promotes sepsis development by impairing PHB1-mediated mitochondrial respiratory chain function

  Relevance score: 6.4059825

  Shi-dong Guo, Sheng-tao Yan, Wen Li, Hong Zhou, Jian-ping Yang, Yao Yao, Mei-jia Shen, Liu-wei Zhang, Hong-Bo Zhang, Li-Chao Sun

  Keywords: HDAC6, PHB1, mitochondrial respiratory control rate, oxidative stress, CLP-induced sepsis

  Published in Aging on March 28, 2020

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  Objective: This study was aimed at investigating the regulation of mitochondrial function by histone deacetylase 6 (HDAC6) and the role of HDAC6 in the development and progression of sepsis.

  Results: HDAC6 downregulated PHB1 and subsequently promoted the development of CLP-induced sepsis. Inhibition of HDAC6 significantly attenuated CLP-induced sepsis through inhibition of mitochondrial dysfunction and reduced oxidant production, thus protecting the rats from oxidative injury.

  Conclusions: In this sepsis model, HDAC6 inhibits the expression and function of PHB1 and alters the function of the mitochondrial respiratory chain mediated by PHB1, thus enhancing the production of oxidants and increasing oxidative stress and thereby leading to severe oxidative injury in multiple organs.

  Methods: The expression of HDAC6 and prohibitin 1 (PHB1) in humans and in a rat model of sepsis was measured by quantitative reverse-transcription PCR and western blotting. Sepsis induction by cecal ligation and puncture (CLP) was confirmed by histological analysis. Concentrations of different sepsis markers were measured by an enzyme-linked immunosorbent assay, and mitochondrial function was assessed via the mitochondrial respiratory control rate.

  

  Expression and correlation of HDAC6 and PHB1 in sepsis patients. Human PBMCs were isolated from healthy control participants and patients with sepsis. HDAC6 and PHB1 mRNA and protein levels were measured by qPCR and western blotting, respectively. The linear correlation between HDAC6 and PHB1 expression was analyzed using the GraphPad Prism software. (A) HDAC6 mRNA; (B) PHB1 mRNA; (C) HDAC6 and PHB1 protein expression; (D) the correlation between HDAC6 and PHB1 expression. Results are expressed as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.

  
  
  

  

  Characterization of CLP-induced sepsis in rats. Serum and tissue samples from rats with untreated CLP-induced sepsis, rats with Tri A–treated CLP sepsis, or healthy control rats. (A) Lung tissue from the control group of rats; (B) lung tissue from rats with CLP-induced sepsis; (C) lung injury index; (D) ALT activity; (E) AST activity; (F) creatinine concentration; and (G) BUN levels in the plasma from healthy control rats and CLP-induced sepsis rats. Results are expressed as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.

  
  
  

  

  HDAC6 and PHB1 expression and oxidative stress in rats with CLP-induced sepsis. (A) HDAC6 mRNA expression; (B) PHB1 mRNA expression; (C) HDAC6 and PHB1 protein expression; (D) MDA levels; (E) SOD activity; and (F) ROS production in CLP-induced sepsis rats and healthy control rats. Results are expressed as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.

  
  
  

  

  HDAC6 can regulate PHB1-mediated mitochondrial respiration. (A) The mitochondrial respiratory control rate; (B) the correlation between the mitochondrial respiratory control rate and PHB1 expression; and (C) the correlation between the mitochondrial respiratory control rate and HDAC6 expression in CLP-induced sepsis rats and healthy control rats. Results are expressed as the mean ± SEM. **P < 0.01.

  
  
  

  

  HDAC6 inhibits the expression of PHB1 and causes subsequent mitochondrial dysfunction. U937 cells were infected with an HDAC6–expressing or HDAC6-specific shRNA–expressing lentivirus, and then gene expression and the mitochondrial respiratory control rate were determined to evaluate the influence of HDAC6 on mitochondrial function. (A) HDAC6 mRNA and protein expression; (B) PHB1 mRNA and protein expression; and (C) the mitochondrial respiratory control rate in lenti-HDAC6 (HDAC6 overexpressing) and lenti-sh-HDAC6 (HDAC6 knockdown) U937 cells. (D) The mitochondrial respiratory control rate in HDAC6 agonist (ITSA1) and HDAC6 inhibitor (Tri A) treated macrophages. Results are expressed as the mean ± SEM. **P < 0.01.

  
  
  

  

  The impact of HDAC6 inhibition on CLP-induced sepsis. Hematoxylin and eosin (H&E)-stained lung tissue sections from rats with CLP-induced sepsis, rats with CLP-induced sepsis treated with Tri A, or control rats (×200 magnification). (A) Lung tissue from control rats; (B) lung tissue from rats with CLP-induced sepsis; (C) lung tissue from rats with CLP-induced sepsis treated with Tri A; (D) the lung injury index of differentially treated rats; (E) ALT activity; (F) AST activity; (G) creatinine concentration; and (H) BUN levels in the plasma from the rats with CLP-induced sepsis, the rats with CLP-induced sepsis treated with Tri A, or the control rats. Results are expressed as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.

  
  
  

• Research Paper pp undefined-undefined

  Hmgcs2 regulates M2 polarization of macrophages to repair myocardial injury induced by sepsis

  Relevance score: 8.995806

  Xiao-Zheng Zou, Jun-Feng Hao, Ming-Xiao Hou

  Keywords: sepsis, CLP, Hmgcs2, M2

  Published in Aging on Invalid Date

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  The respiratory and cardiovascular systems are often the most severely impacted by the rapid onset of sepsis, which can lead to multiple organ failure. The mortality has ranged from 10 to 40% when it has evolved into septic shock. This study sought to demonstrate the potential and role of Hmgcs2 in safeguarding against cardiovascular harm in septic mouse models.

  The cecal ligament and puncture (CLP) model was used to induce sepsis in C57BL/6 mice, with Hmgcs2 expression in the myocardium of the mice being heightened and inflammatory factors being augmented. Subsequently, we utilized ASOs to silence the hmgcs2 gene, and found that silencing accelerated septic myocardial injury and cardiac dysfunction in CLP mice models. In contrast, hmgcs2 attenuated inflammation and apoptosis and protected against septic cardiomyopathy in murine septicemia models. Src production, spurred on by Hmgcs2, triggered the PI3K/Akt pathway and augmented M2 macrophage polarization. Moreover, the inhibition of M2 polarization by an Src antagonist significantly contributed to apoptosis of cardiomyocytes.

  Our research revealed that Hmgcs2 inhibited the activation of pro-inflammatory macrophages and, through Src-dependent activation of PI3K/Akt pathway, promoted the anti-inflammatory phenotype, thus safeguarding myocardial damage from sepsis. This offers a novel theoretical basis for prevention and treatment of infectious complications.