Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells

• Published in: Vascular pharmacology Vol. 154; p. 107279
• Main Authors: Yap, Carmen, Wanga, Shaynah, Wüst, Rob C.I., van Os, Bram W., Pijls, Maud M.E., Keijzer, Sofie, van Zanten, Eva, Koolbergen, David R., Driessen, Antoine H.G., Balm, Ron, Yeung, Kak Khee, de Vries, Carlie J.M., Houtkooper, Riekelt H., Lindeman, Jan H.N., de Waard, Vivian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2024
• Subjects: Aorta - metabolism; Aortic aneurysm; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - prevention & control; Cardiovascular; Cellular phenotype; Doxycycline - adverse effects; Doxycycline - metabolism; Elamipretide (SS-31); Humans; Metabolism; Mitochondria; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Myocytes, Smooth Muscle - metabolism; Smooth muscle cell; Smooth muscle cell; Mitochondria; Cellular phenotype; Metabolism; Aortic aneurysm; Elamipretide (SS-31)
• ISSN: 1537-1891; 1879-3649; 1879-3649
• DOI: 10.1016/j.vph.2024.107279

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. [Display omitted]