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Inhibition Of Matrix Metalloproteinase-9 Does Not Suppress Aortic Dilatation Caused By Tobacco Smoke Exposure

Amy E Hackmann, Batool Arif, Monica B. Pagano, Terri L. Ennis, Robert W. Thompson, John A. Curci ∙ Washington University School of Medicine, St. Louis, MO

Objective: Prior studies of abdominal aortic aneurysms (AAAs) in SvEv mice have shown progressive dilatation of the aorta in smoke exposed mice that is not seen in control mice. To assess whether the effects of smoking result from an amplification of the Matrix Metalloproteinase (MMP) dependent processes known to be associated with this model, we examined the effects of pharmacologic suppression and genetic deletion of MMP-9 on AAA development.
Methods: Male SvEv mice, both wild-type and MMP 9 -/-, were exposed to either cigarette smoke or smoke-free conditions for four weeks. Following intraaortic elastase perfusion, the mice continued under the same conditions for an additional two weeks. A subset of wild-type mice was given doxycycline (100 mg/kg/day) via their drinking water from the day of surgery until sacrifice. At sacrifice, the aortic diameter was measured in vivo.
Results: As seen previously at this early time-point, there is a small but non-significant difference in aortic diameters between smoke-exposed (126.72 + 5.30%; N=19) and control wild-type mice (116.11 + 5.05%; N=18). Among mice treated with doxycycline, the smoke-exposed mice (N=9) developed aneurysms which were significantly larger than the control mice (N=7) (128.89 + 3.51% versus 104.34 + 4.34%; P=.0006). This was primarily related to a modest reduction in the size of the AAAs in control mice treated with doxycycline, while doxycycline had no effect on the aortic diameters of the smoke exposed mice. (See Figure) Furthermore, in MMP-9 -/- mice there persisted a significant difference in AAA size between the smoke-exposed (N=8) and unexposed (N=8) mice, despite considerable inhibition in the overall dilatation in both groups. (88.75 + 3.50% versus 66.48 + 2.74%; P=.0002). All values are expressed as the mean percentage change in aortic diameter plus or minus the standard error of the mean.
Conclusions: While MMP-9 is critical for aneurysm development, cigarette smoke exposure may act through alternative pathways to promote aortic dilatation. Smoke exposure in mice results in larger aneurysms despite broad inhibition of the MMPs with doxycycline or MMP-9 enzyme deficiency. In the clinical setting, pharmacologic inhibition of the MMPs may be a less effective suppressive therapy for AAAs in patients who continue to smoke cigarettes.