Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: United States NLM ID: 101130615 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-3649 (Electronic) Linking ISSN: 15371891 NLM ISO Abbreviation: Vascul Pharmacol Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York, NY : Elsevier Science, c2002-
    • Subject Terms:
      Aortic Aneurysm, Abdominal*/chemically induced ; Aortic Aneurysm, Abdominal*/prevention & control ; Aortic Aneurysm, Abdominal*/genetics ; Mitochondrial Diseases*/metabolism ; Mitochondrial Diseases*/pathology; Humans ; Doxycycline/adverse effects ; Doxycycline/metabolism ; Aorta/metabolism ; Myocytes, Smooth Muscle/metabolism
    • Abstract:
      The antibiotic doxycycline is known to inhibit inflammation and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. Yet mitochondrial dysfunction is a key-characteristic of clinical AAA disease. We hypothesize that doxycycline impairs mitochondrial function in the aorta and aortic smooth muscle cells (SMCs). Doxycycline induced mitonuclear imbalance, reduced proliferation and diminished expression of typical contractile smooth muscle cell (SMC) proteins. To understand the underlying mechanism, we studied krüppel-like factor 4 (KLF4). The expression of this transcription factor was enhanced in SMCs after doxycycline treatment. Knockdown of KLF4, however, did not affect the doxycycline-induced SMC phenotypic changes. Then we used the bioenergetics drug elamipretide (SS-31). Doxycycline-induced loss of SMC contractility markers was not rescued, but mitochondrial genes and mitochondrial connectivity improved upon elamipretide. Thus while doxycycline is anti-inflammatory, it also induces mitochondrial dysfunction in aortic SMCs and causes SMC phenotypic switching, potentially contributing to aortic aneurysm pathology. The drug elamipretide helps mitigate the harmful effects of doxycycline on mitochondrial function in aortic SMC, and may be of interest for treatment of aneurysm diseases with pre-existing mitochondrial dysfunction.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Aortic aneurysm; Cellular phenotype; Elamipretide (SS-31); Metabolism; Mitochondria; Smooth muscle cell
    • Accession Number:
      N12000U13O (Doxycycline)
    • Publication Date:
      Date Created: 20240125 Date Completed: 20240311 Latest Revision: 20240430
    • Publication Date:
      20240501
    • Accession Number:
      10.1016/j.vph.2024.107279
    • Accession Number:
      38272196