Abstract 14703: Angiotensin Receptor Blockade Positively Regulates MMP2 and TIMP1 in Patients With Aortic Aneurysms
Background: Matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) play an important role in extracellular matrix (ECM) remodeling, and have been implicated in aortic aneurysm (AA) formation. Angiotensin II type 1 receptor blockers (ARB) may slow progression of AA through selective inhibition of AT1 receptor signaling and downstream effects on MMP expression. We hypothesized that non-syndromic AA patients display altered levels of MMP and/or TIMP, which may further be altered with ARB therapy.
Methods: Maximally dilated AA sections were collected on patients undergoing aortic root replacement at the time of surgery. Protein levels of MMP2, MMP9, MMP12, TIMP1, and TIMP4 were analyzed in patients on ARBs (n=11) and patients with AAs not on ARBs (n = 13) using Western blotting. Aortic samples collected from heart transplant donors were used as normal controls (n=11). Maximal AA diameter was measured by preoperative computed tomography or intraoperative transesophageal echocardiography.
Results: Levels of MMP2 were significantly higher in the non-ARB group compared to normal (+2.5 fold, p=0.004) while ARB therapy partially reduced this effect (+1.6 fold vs. normal, p=0.033) (Table 1). TIMP1 levels were significantly decreased in ARB and non-ARB patients compared to normal (-76%, p=0.010 and -69%, p =0.031, respectively). There were no significant differences seen in MMP9, MMP12, or TIMP4. A higher ratio of MMP2:TIMP1 in non-ARB was present compared to those on ARBs and normal patients (3.6 versus 2.13 in non-ARB, p=0.035, and 1.02 in normals, p=0.005 vs. non-ARB).
Conclusion: Increased MMP-2 and reduced TIMP1 in non-syndromic AA may alter ECM integrity and worsen aneurysmal dilatation. ARB therapy may serve to limit aortic expansion in part by normalization of the MMP2:TIMP1 ratio. These findings may support ARB therapy for small and intermediate sized AAs.
- © 2013 by American Heart Association, Inc.