TY - JOUR
T1 - Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells
AU - Yap, Carmen
AU - Wanga, Shaynah
AU - Wüst, Rob C. I.
AU - van Os, Bram W.
AU - Pijls, Maud M. E.
AU - Keijzer, Sofie
AU - van Zanten, Eva
AU - Koolbergen, David R.
AU - Driessen, Antoine H. G.
AU - Balm, Ron
AU - Yeung, Kak Khee
AU - de Vries, Carlie J. M.
AU - Houtkooper, Riekelt H.
AU - Lindeman, Jan H. N.
AU - de Waard, Vivian
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024/3/1
Y1 - 2024/3/1
N2 - 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.
AB - 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.
KW - Aortic aneurysm
KW - Cellular phenotype
KW - Elamipretide (SS-31)
KW - Metabolism
KW - Mitochondria
KW - Smooth muscle cell
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85184081187&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/38272196
UR - http://www.scopus.com/inward/record.url?scp=85184081187&partnerID=8YFLogxK
U2 - 10.1016/j.vph.2024.107279
DO - 10.1016/j.vph.2024.107279
M3 - Article
C2 - 38272196
SN - 1537-1891
VL - 154
JO - Vascular Pharmacology
JF - Vascular Pharmacology
M1 - 107279
ER -