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Mechanisms of TFAM-mediated cardiomyocyte protection.

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  • معلومة اضافية
    • المصدر:
      Publisher: Canadian Science Publishing Country of Publication: Canada NLM ID: 0372712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1205-7541 (Electronic) Linking ISSN: 00084212 NLM ISO Abbreviation: Can J Physiol Pharmacol Subsets: MEDLINE
    • بيانات النشر:
      Publication: 2011- : Ottawa, ON : Canadian Science Publishing
      Original Publication: Ottawa, National Research Council of Canada.
    • الموضوع:
      DNA-Binding Proteins/*metabolism ; Mitochondrial Proteins/*metabolism ; Myocytes, Cardiac/*metabolism ; Transcription Factors/*metabolism; Animals ; CRISPR-Cas Systems/genetics ; Calpain/metabolism ; Cell Line ; Hydrogen Peroxide/pharmacology ; Matrix Metalloproteinase 9/metabolism ; Mice ; Myocytes, Cardiac/drug effects ; NFATC Transcription Factors/metabolism ; Peptide Hydrolases/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases
    • نبذة مختصرة :
      Although mitochondrial transcription factor A (TFAM) is a protective component of mitochondrial DNA and a regulator of calcium and reactive oxygen species (ROS) production, the mechanism remains unclear. In heart failure, TFAM is significantly decreased and cardiomyocyte instability ensues. TFAM inhibits nuclear factor of activated T cells (NFAT), which reduces ROS production; additionally, TFAM transcriptionally activates SERCA2a to decrease free calcium. Therefore, decreasing TFAM vastly increases protease expression and hypertrophic factors, leading to cardiomyocyte functional decline. To examine this hypothesis, treatments of 1.0 μg of a TFAM vector and 1.0 μg of a CRISPR-Cas9 TFAM plasmid were administered to HL-1 cardiomyocytes via lipofectamine transfection. Western blotting and confocal microscopy analysis show that CRISPR-Cas9 knockdown of TFAM significantly increased proteases Calpain1, MMP9, and regulators Serca2a, and NFAT4 protein expression. CRISPR knockdown of TFAM in HL-1 cardiomyocytes upregulates degradation factors, leading to cardiomyocyte instability. Hydrogen peroxide oxidative stress decreased TFAM expression and increased Calpain1, MMP9, and NFAT4 protein expression. TFAM overexpression normalizes pathological hypertrophic factor NFAT4 in the presence of oxidative stress.
    • Grant Information:
      F31 HL132527 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: Calpain1; H2O2; MMP9; NFAT; Serca2a; TFAM; calpaïne 1
    • الرقم المعرف:
      0 (DNA-Binding Proteins)
      0 (Mitochondrial Proteins)
      0 (NFATC Transcription Factors)
      0 (Transcription Factors)
      0 (mitochondrial transcription factor A)
      BBX060AN9V (Hydrogen Peroxide)
      EC 3.4.- (Peptide Hydrolases)
      EC 3.4.22.- (Calpain)
      EC 3.4.24.35 (Matrix Metalloproteinase 9)
      EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
    • الموضوع:
      Date Created: 20170812 Date Completed: 20180810 Latest Revision: 20191008
    • الموضوع:
      20221213
    • الرقم المعرف:
      10.1139/cjpp-2016-0718
    • الرقم المعرف:
      28800400