Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells

Vascular Pharmacology, vol. 154, pp. 107279

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.

Authors 15

1. Carmen Yap

   Amsterdam UMC Location University of Amsterdam · Amsterdam Cardiovascular Sciences

   Affiliation as printed

   Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands

   Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands

   Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands

2. Shaynah Wanga

   Amsterdam UMC Location University of Amsterdam

   Affiliation as printed

   Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Cardiology, Meibergdreef 9, Amsterdam, the Netherlands

   Amsterdam UMC location University of Amsterdam, Cardiology, Meibergdreef 9, Amsterdam, the Netherlands

   Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands

3. Rob C. I. Wüst

   Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Amsterdam UMC location Vrije Universiteit Amsterdam, Behavioural and Movement Sciences, Myology, Boelelaan 1117, Amsterdam, the Netherlands

4. Bram W. van Os

   Amsterdam UMC Location University of Amsterdam

   Affiliation as printed

   Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands

5. Maud M. E. Pijls

   Amsterdam UMC Location University of Amsterdam

   Affiliation as printed

   Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands

6. Sofie Keijzer

   Amsterdam UMC Location University of Amsterdam

   Affiliation as printed

   Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands

7. Eva van Zanten

   Amsterdam UMC Location University of Amsterdam

   Affiliation as printed

   Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands

8. David R. Koolbergen

   Amsterdam UMC Location University of Amsterdam

   Affiliation as printed

   Amsterdam UMC location University of Amsterdam, Cardiothoracic Surgery, Meibergdreef 9, Amsterdam, the Netherlands

9. Antoine H.G. Driessen

   Amsterdam UMC Location University of Amsterdam

   Affiliation as printed

   Amsterdam UMC location University of Amsterdam, Cardiothoracic Surgery, Meibergdreef 9, Amsterdam, the Netherlands

10. Ron Balm

    Amsterdam UMC Location University of Amsterdam

    Affiliation as printed

    Amsterdam UMC location University of Amsterdam, Vascular Surgery, Meibergdreef 9, Amsterdam, the Netherlands

11. Kak Khee Yeung

    Amsterdam UMC Location University of Amsterdam · Amsterdam Cardiovascular Sciences · Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Vascular Surgery, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Physiology, De Boelelaan 1117, Amsterdam, Netherlands

    Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands

    Amsterdam UMC location University of Amsterdam, Vascular Surgery, Meibergdreef 9, Amsterdam, the Netherlands

    Amsterdam UMC location Vrije Universiteit Amsterdam, Physiology, De Boelelaan 1117, Amsterdam, Netherlands

12. Carlie J.M. de Vries

    Amsterdam UMC Location University of Amsterdam · Amsterdam Cardiovascular Sciences

    Affiliation as printed

    Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands

    Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands

    Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands

13. Riekelt H. Houtkooper

    Amsterdam UMC Location University of Amsterdam · Amsterdam Gastroenterology Endocrinology Metabolism · Amsterdam Cardiovascular Sciences

    Affiliation as printed

    Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology, and Metabolism, Amsterdam, the Netherlands

    Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands

    Amsterdam Gastroenterology Endocrinology, and Metabolism, Amsterdam, the Netherlands

    Amsterdam UMC location University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, the Netherlands

14. Jan H.N. Lindeman Aachen Vascular Surgery

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center, Vascular Surgery, Leiden, the Netherlands

15. Vivian de Waard corresponding

    Amsterdam UMC Location University of Amsterdam · Amsterdam Cardiovascular Sciences

    Affiliation as printed

    Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands. Electronic address: v.dewaard@amsterdamumc.nl

    Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands

    Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Meibergdreef 9, Amsterdam, the Netherlands