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Hazem Abdul-Hussien1, Roeland Hanemaaijer, Jan H Verheijen
1Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Background:
Matrix metalloproteinase-9 (MMP-9) is thought to play a central role in abdominal aortic aneurysm (AAA) initiation. Doxycycline, a tetracycline analogue, has direct MMP-9-inhibiting properties in vitro, and it effectively suppresses AAA development in rodents. Observed inhibition of AAA progression, and contradictory findings in human studies evaluating the effect of doxycycline therapy on aortic wall MMP-9, suggest that the effects of doxycycline extend beyond MMP-9 inhibition and that the effect may be dose-dependent.
Methods:
This clinical trial evaluated the effect of 2 weeks of low- (50 mg/d), medium- (100 mg/d), or high-dose (300 mg/d) doxycycline vs no medication in four groups of 15 patients undergoing elective AAA repair. The effect of doxycycline treatment on MMP and cysteine proteases, and their respective inhibitors, was evaluated by quantitative polymerase chain reaction, Western blot analysis, immunocapture protease activity assays, and immunohistochemistry.
Results:
Doxycycline was well tolerated and no participants dropped out. Doxycycline treatment reduced aortic wall MMP-3 and MMP-25 messenger RNA expression (P < .045 and P < .014, respectively), selectively suppressed neutrophil collagenase and gelatinase (MMP-8 and MMP-9) protein levels (P < .013 and <.004, respectively), and increased protein levels of the protease inhibitors tissue inhibitor of metalloproteinase 1 and cystatin C (P < .029). As for the apparent selective effect on neutrophil-associated proteases, we sought for a reducing effect on aortic wall neutrophil content that was indeed confirmed by immunohistochemical analysis that revealed a 75% reduction in aneurysm wall neutrophil content (P < .001).
Conclusions:
Independent of its dose, short-term preoperative doxycycline therapy improves the proteolytic balance in AAA, presumably through an effect on aortic wall neutrophil content. This study provides a rationale for doxycycline treatment in patients with an AAA as well as in other (vascular) conditions involving neutrophil influx such as Kawasaki disease and Behçet disease.
Insights
Short-term doxycycline therapy improves abdominal aortic aneurysm (AAA) proteolytic balance by reducing aortic wall neutrophils, independent of dose. This suggests potential benefits for AAA and other neutrophil-driven vascular conditions.
Area of Science:
- Vascular Biology
- Matrix Metalloproteinases
- Pharmacology
Background:
- Matrix metalloproteinase-9 (MMP-9) is implicated in abdominal aortic aneurysm (AAA) initiation.
- Doxycycline inhibits MMP-9 in vitro and suppresses AAA in rodents.
- Human studies show variable effects of doxycycline on aortic MMP-9, suggesting broader or dose-dependent mechanisms.
Purpose of the Study:
- To evaluate the dose-dependent effects of short-term doxycycline therapy on AAA.
- To investigate doxycycline's impact on matrix proteases, cysteine proteases, and their inhibitors in the aortic wall.
- To assess doxycycline's influence on neutrophil content within the aneurysm wall.
Main Methods:
- A clinical trial involving 4 groups of 15 patients undergoing elective AAA repair received low (50 mg/d), medium (100 mg/d), high-dose (300 mg/d) doxycycline, or no medication for 2 weeks.
- Quantitative PCR, Western blot, immunocapture assays, and immunohistochemistry were used to analyze protease and inhibitor levels and neutrophil content.
Main Results:
- Doxycycline was well-tolerated with no dropouts.
- Treatment reduced MMP-3 and MMP-25 mRNA, and selectively suppressed MMP-8 and MMP-9 protein levels.
- Doxycycline increased tissue inhibitor of metalloproteinase 1 and cystatin C protein levels and reduced aneurysm wall neutrophil content by 75%.
Conclusions:
- Short-term preoperative doxycycline therapy, irrespective of dose, enhances proteolytic balance in AAA.
- The mechanism is likely related to a reduction in aortic wall neutrophil content.
- This supports doxycycline as a potential treatment for AAA and other neutrophil-related vascular conditions like Kawasaki and Behçet diseases.
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