Published online before print April 3, 2008, doi: 10.1161/CIRCRESAHA.108.174367
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 16, 2007
Revised on March 24, 2008
Accepted on March 26, 2008
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 *;
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.
* To whom correspondence should be addressed. E-mail: achung{at}mrl.ubc.ca.
-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 (Fbn1C1039G/+) 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- 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- activation.
Key words: doxycycline • atenolol • thoracic aortic aneurysm • Marfan syndrome • matrix metalloproteinase
This article has been cited by other articles:
 |
|
 |
|
  J. Huang, E. C. Davis, S. L. Chapman, M. Budatha, L. Y. Marmorstein, R. A. Word, and H. Yanagisawa Fibulin-4 Deficiency Results in Ascending Aortic Aneurysms: A Potential Link Between Abnormal Smooth Muscle Cell Phenotype and Aneurysm Progression Circ. Res., February 19, 2010; 106(3): 583 - 592. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Pilop, F. Aregger, R. C. Gorman, R. Brunisholz, B. Gerrits, T. Schaffner, J. H. Gorman III, G. Matyas, T. Carrel, and B. M. Frey Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms Circulation, September 15, 2009; 120(11): 983 - 991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W.Y. Chung, H.H. C. Yang, J. M. Kim, M. K. Sigrist, E. Chum, W. A. Gourlay, and A. Levin Upregulation of Matrix Metalloproteinase-2 in the Arterial Vasculature Contributes to Stiffening and Vasomotor Dysfunction in Patients With Chronic Kidney Disease Circulation, September 1, 2009; 120(9): 792 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Matt, F. Schoenhoff, J. Habashi, T. Holm, C. Van Erp, D. Loch, O. D. Carlson, B. F. Griswold, Q. Fu, J. De Backer, et al. Circulating Transforming Growth Factor-{beta} in Marfan Syndrome Circulation, August 11, 2009; 120(6): 526 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Braverman Transforming Growth Factor-{beta}: A Biomarker in Marfan Syndrome? Circulation, August 11, 2009; 120(6): 464 - 466. [Full Text] [PDF]
|
|
|
|
 |
|
 L. V. Gulotta, J. R. Rudzki, D. Kovacevic, C. C. T. Chen, D. Milentijevic, and R. J. Williams III Chondrocyte Death and Cartilage Degradation After Autologous Osteochondral Transplantation Surgery in a Rabbit Model Am. J. Sports Med., July 1, 2009; 37(7): 1324 - 1333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ramirez and H. C. Dietz Extracellular Microfibrils in Vertebrate Development and Disease Processes J. Biol. Chem., May 29, 2009; 284(22): 14677 - 14681. [Full Text] [PDF]
|
|
|
|
|
|
L. Carta, S. Smaldone, L. Zilberberg, D. Loch, H. C. Dietz, D. B. Rifkin, and F. Ramirez p38 MAPK Is an Early Determinant of Promiscuous Smad2/3 Signaling in the Aortas of Fibrillin-1 (Fbn1)-null Mice J. Biol. Chem., February 27, 2009; 284(9): 5630 - 5636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E Pyeritz Marfan syndrome: 30 years of research equals 30 years of additional life expectancy Heart, February 1, 2009; 95(3): 173 - 175. [Full Text] [PDF]
|
|
|
|
 |
|
 J. West, J. Harral, K. Lane, Y. Deng, B. Ickes, D. Crona, S. Albu, D. Stewart, and K. Fagan Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L744 - L755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Ahimastos, A. M. Dart, B. A. Kingwell, S. A. Jimenez, J. Rosenbloom, F. S. van Dijk, H. Meijers-Heijboer, G. Pals, B. S. Brooke, and H. C. Dietz III Angiotensin II Blockade in Marfan's Syndrome N. Engl. J. Med., October 16, 2008; 359(16): 1732 - 1734. [Full Text] [PDF]
|
|