Doxycycline inhibits elastin degradation and reduces metalloproteinase activity in a model of aneurysmal disease.
OBJECTIVE
Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These changes are mediated by increased levels of endogenous metalloproteinases (MMPs) within the aorta, which provide a potential therapeutic target for pharmacologic agents aimed at reducing the growth rate of small aneurysms. In this study, the ability of doxycycline--an MMP inhibitor--to reduce matrix degradation was assessed in a previously described model of aneurysmal disease that used a brief pulse of elastase to induce MMP production and elastin degradation in arterial organ cultures.


METHODS
Porcine aortic segments (n = 8) were preincubated in exogenous pancreatic elastase for 24 hours before culture in standard conditions for 13 days with both 1 and 10 mg/L doxycycline. Control segments were cultured both without doxycycline and without elastase. At the termination of culture, MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereologic analysis of sections stained with Miller's elastin and van Gieson's stain.


RESULTS
Stereologic analysis demonstrated a significant preservation of elastin in aorta treated with doxycycline 10 mg/L (p < 0.001) and demonstrated that this preservation was accompanied by a significant reduction in MMP-9 activity (p < 0.02). Immunoblotting for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) showed no decreased production in the doxycycline-treated groups.


CONCLUSIONS
Therapeutic ranges of doxycycline significantly inhibited elastin degradation and MMP-9 production within aortic organ cultures. These data suggest that doxycycline may have a potential application in reducing the growth rates of small abdominal aortic aneurysms.
Boyle
J R
JR
Department of Surgery, Leicester University, United Kingdom.
McDermott
E
E
Crowther
M
M
Wills
A D
AD
Bell
P R
PR
Thompson
M M
MM
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D017545:Aortic Aneurysm, Thoracic / Q000188:drug therapy* / Q000473:pathology; D004318:Doxycycline / Q000494:pharmacology*; D004549:Elastin / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009924:Organ Culture Techniques; D013552:Swine
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D004549:Elastin; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline