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(Circulation Research. 2007;101:512.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Loss of Elastic Fiber Integrity and Reduction of Vascular Smooth Muscle Contraction Resulting From the Upregulated Activities of Matrix Metalloproteinase-2 and -9 in the Thoracic Aortic Aneurysm in Marfan Syndrome

Ada W.Y. Chung, Karen Au Yeung, George G.S. Sandor, Daniel P. Judge, Harry C. Dietz, Cornelis van Breemen

From the Child and Family Research Institute (A.W.Y.C., K.A.Y., C.v.B.) and Department of Anesthesiology, Pharmacology and Therapeutics (A.W.Y.C., K.A.Y., C.v.B.); Division of Cardiology (G.G.S.S.), Department of Pediatrics, British Columbia Children’s Hospital, University of British Columbia, Vancouver, Canada; and Howard Hughes Medical Institute and the Institute of Genetic Medicine (D.P.J., H.C.D.), Johns Hopkins University School of Medicine, Baltimore, Md.

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

Thoracic aortic aneurysm (TAA) is the life-threatening complication of Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 gene. TAA is characterized by degradation of elastic fiber, suggesting the involvement of matrix metalloproteinase (MMP)-2 and -9, the activation of which is regulated by TIMP (tissue inhibitor of MMP) types 1 and 2. We hypothesized that MMP-2 and -9 were upregulated during TAA formation in Marfan syndrome, causing loss of elastic fibers and structural integrity. We studied mice, from 3 to 12 months, heterozygous for a mutant Fbn1 allele encoding a cysteine substitution in fibrillin-1 (Fbn1^C1039G/+, designated as "Marfan" mice) (n=120), the most common class of mutation in Marfan syndrome. The littermates, Fbn1^+/+ served as controls (n=120). In Marfan aneurysmal thoracic aorta, mRNA and protein expression of MMP-2 and -9 were detected at 3 months and peaked at 6 months of age, accompanied by severe elastic fiber fragmentation and degradation. From 3 to 9 months, the MMP-2/TIMP-2 ratio increased by 43% to 63% compared with the controls. Dilated thoracic aorta demonstrated increased elasticity but distention caused a pronounced loss of contraction, suggesting weakening of the aortic wall. Breaking stress of the aneurysmal aorta was 70% of the controls. Contraction in response to depolarization and receptor stimulation decreased in the aneurysmal thoracic aorta by 50% to 80%, but the expression of -smooth muscle actin between the 2 strains was not significantly different. This report demonstrates the upregulation of MMP-2 and -9 during TAA formation in Marfan syndrome. The resulting elastic fiber degeneration with deterioration of the aortic contraction and mechanical properties may explain the pathogenesis of TAA.

Key Words: thoracic aortic aneurysm • Marfan syndrome • elastic fiber • matrix metalloproteinase • vascular smooth muscle contraction

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