Abstract 533: Doxycycline Fuels Mitochondrial Dysfunction In Aortic Smooth Muscle Cells

Arteriosclerosis Thrombosis and Vascular Biology, vol. 43

Abstract

Introduction: The antibiotic doxycycline is known to inhibit inflammation, and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. However, in two clinical trials, doxycycline-treated AAA patients did not experience reduced aneurysm growth. Doxycycline was previously shown to induce mitonuclear imbalance and reduce mitochondrial function. Objective: To determine that doxycycline would also impair mitochondrial function in the aorta and aortic smooth muscle cells (SMCs), giving rise to SMC phenotype switching. Results: Oral doxycycline intake induced mitonuclear imbalance in the murine aorta, human aortic aneurysm tissue and in human aortic SMCs. Consequently, doxycycline reduced mitochondrial activity and respiration in aortic SMCs. Transcription factor krüppel-like factor 4 (KLF4), a player in mitochondrial homeostasis, is upregulated after doxycycline treatment. Moreover, the integrated stress response effector, activating transcription factor 4 (ATF4), is enhanced to restore cellular homeostasis. These changes result in diminished expression of typical contractile SMC markers. Treatment with the drug Elamipretide (SS-31) improves mitochondrial markers and cellular stress management. Conclusion: Doxycycline leads to mitochondrial dysfunction and ER stress in aortic SMCs. These changes may contribute to aortic aneurysm growth by impairing SMC function. Elamipretide offers rescue from some of the harmful effects of doxycycline by improving mitochondrial function.

Authors 8

1. Carmen Yap
   Affiliation as printed

   Amsterdam Med Cntr, Amsterdam, Netherlands

   Carmen Yap Amsterdam Med Cntr, Amsterdam, Netherlands

2. Shaynah Wanga
   Affiliation as printed

   Amsterdam Med Cntr, Amsterdam, Netherlands

   Shaynah Wanga Amsterdam Med Cntr, Amsterdam, Netherlands

3. Antoine H.G. Driessen

   Amsterdam University Medical Centers

   Affiliation as printed

   Amsterdam Med Cntr, Amsterdam, Netherlands

   Antoine Driessen Amsterdam Med Cntr, Amsterdam, Netherlands

4. Rob C. I. Wüst
   Affiliation as printed

   Amsterdam Med Cntr, Amsterdam, Netherlands

5. Carlie J.M. de Vries
   Affiliation as printed

   Amsterdam Med Cntr, Amsterdam, Netherlands

   Carlie J de Vries Amsterdam Med Cntr, Amsterdam, Netherlands

6. Riekelt H Houtkoper
   Affiliation as printed

   Amsterdam Med Cntr, Amsterdam, Netherlands

   Riekelt H Houtkoper Amsterdam Med Cntr, Amsterdam, Netherlands

7. Jan H Lindeman Aachen Jan H Lindeman Leiden Univ Med Cntr

   Leiden University

   Affiliation as printed

   Leiden Univ Med Cntr, Leiden, Netherlands

   Jan H Lindeman Leiden Univ Med Cntr, Leiden, Netherlands

8. Vivian de Waard
   Affiliation as printed

   Amsterdam Med Cntr, Amsterdam, Netherlands

   Vivian De Waard Amsterdam Med Cntr, Amsterdam, Netherlands