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(Circulation Research. 2008;102:e73.)
© 2008 American Heart Association, Inc.

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Long-Term Doxycycline Is More Effective Than Atenolol to Prevent Thoracic Aortic Aneurysm in Marfan Syndrome Through the Inhibition of Matrix Metalloproteinase-2 and -9

Ada W.Y. Chung, H. H. Clarice Yang, Marek W. Radomski, Cornelis van Breemen

From the Child and Family Research Institute (A.W.Y.C., H.H.C.Y., C.V.B.), Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada; and School of Pharmacy and Pharmaceutical Sciences (M.W.R.), Trinity College, Dublin, Ireland.

Correspondence to Ada W.Y. Chung, PhD, Cardiovascular Science, Room 2099, 950 28th W Ave, Vancouver, British Columbia, Canada V5Z 4H4. E-mail achung{at}mrl.ubc.ca

β-Blockers, eg, atenolol, are the cornerstone therapy for thoracic aortic aneurysm (TAA) in patients with Marfan syndrome; however, continued aortic dilatation has been reported. We have demonstrated that matrix metalloproteinase (MMP)-2 and -9 were upregulated during progression of TAA in Marfan syndrome, accompanied with degenerated elastic fibers and vasomotor dysfunction. We hypothesized that doxycycline, a nonspecific inhibitor of MMPs, would ameliorate TAA by attenuating elastic fiber degeneration and improving vasomotor function. A well-characterized mouse model of Marfan syndrome (Fbn1^C1039G/+) was used. Mice were untreated (n=40), given doxycycline (0.24g/L, n=30), or given atenolol (0.5g/L, n=30) in drinking water at 6 weeks of age. The Fbn1^+/+ mice served as control (n=40). At 3, 6, and 9 months, aortic segments from the ascending, arch, and descending portions were used to obtain the "average" value of the whole thoracic aorta. TAA was prevented in the doxycycline group, whereas mild aneurysm was evident in the atenolol group. Doxycycline improved elastic fiber integrity, normalized aortic stiffness, and prevented vessel weakening. The impairment of vasocontraction and endothelium-dependent relaxation in the untreated and atenolol groups were improved by doxycycline. The upregulation of transforming growth factor-β in the Marfan aorta was suppressed by doxycycline. Doxycycline augmented expression ratios of tissue inhibitors of MMP to MMPs. Intraperitoneally injected neutralizing antibodies against MMP-2 and -9 yielded similar effects to doxycycline. We concluded that long-term treatment with doxycycline, through the inhibition of MMP-2 and -9, is more effective than atenolol in preventing TAA in Marfan syndrome by preserving elastic fiber integrity, normalizing vasomotor function, and reducing transforming growth factor-β activation.

Key Words: doxycycline • atenolol • thoracic aortic aneurysm • Marfan syndrome • matrix metalloproteinase