title: N-Acetyl Cysteine improves the diabetic cardiac function: possible role of fibrosis inhibition.
abstract: BACKGROUND
  Diabetic cardiomyopathy is one of the leading causes of death in diabetes mellitus (DM) patients. This study aimed to explore the therapeutic implication of N-acetyl-L-cysteine (NAC, an antioxidant and glutathione precursor) and the possible underlying mechanism.
  
  
  METHODS
  Thirty five 12-week-old male C57BL/6 mice were included. Twenty-five diabetic mice were induced by intraperitoneal injection of streptozocin (STZ, 150 mg/kg, Sigma-Aldrich) dissolved in a mix of citrate buffer after overnight fast. Mice with a blood glucose level above 13.5 mmol/L were considered diabetic. As a non-DM (diabetic) control, mice were injected with equal volume of citrate buffer. The 25 diabetic mice were divided into 5 groups with 5 animals in each group: including DM (diabetes without NAC treatment), and 4 different NAC treatment groups, namely NAC1, NAC3, NAC5 and NAC7, with the number defining the start time point of NAC treatment. In the 10 non-DM mice, mice were either untreated (Ctrl) or treated with NAC for 5 weeks (NAC only). Echocardiography was performed 12 weeks after STZ injection. Heart tissue were collected after echocardiography for Hematoxylin Eosin (HE) and Trichrome staining and ROS staining. Cardiac fibroblast cells were isolated, cultured and treated with high glucose plus NAC or the vehicle. qPCR analysis and CCK-8 assay were performed to observe fibrotic gene expression and cell proliferation.
  
  
  RESULTS
  We found that both cardiac systolic function and diastolic function were impaired, coupled with excessive reactive oxygen stress and cardiac fibrosis 12 weeks after STZ induction. NAC significantly reduced ROS generation and fibrosis, together with improved cardiac systolic function and diastolic function. Strikingly, NAC1 treatment, which had the earlier and longer treatment, produced significant improvement of cardiac function and less fibrosis. In the cardiac fibroblasts, NAC blocked cardiac fibroblast proliferation and collagen synthesis induced by hyperglycemia.
  
  
  CONCLUSIONS
  Our study indicates that NAC treatment in diabetes effectively protects from diabetic cardiomyopathy, possibly through inhibiting the ROS production and fibrosis, which warrants further clarification.
authors.affiliation: Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, #569 Xinsi Road, Baqiao District, Xi'an, 710038, China. 1821216564@qq.com.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China. fe_head@live.cn.
authors.forename: Xiao-Zhao
authors.initials: XZ
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China. 1546208837@qq.com.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Shen
authors.affiliation: Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, #569 Xinsi Road, Baqiao District, Xi'an, 710038, China. 349514853@qq.com.
authors.forename: Chang-Yang
authors.initials: CY
authors.lastname: Xing
authors.affiliation: Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, #569 Xinsi Road, Baqiao District, Xi'an, 710038, China. 178937707@qq.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, #569 Xinsi Road, Baqiao District, Xi'an, 710038, China. duanyy@fmmu.edu.cn.
authors.forename: Yun-You
authors.initials: YY
authors.lastname: Duan
authors.affiliation: Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, #569 Xinsi Road, Baqiao District, Xi'an, 710038, China. yuanlj@fmmu.edu.cn.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yuan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology
chemical_list: D000111:Acetylcysteine