Abstract-␤-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/ϩ ) was used. Mice were untreated (nϭ40), given doxycycline (0.24g/L, nϭ30), or given atenolol (0.5g/L, nϭ30) in drinking water at 6 weeks of age. The Fbn1 ϩ/ϩ mice served as control (nϭ40). 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. (FBN-1). 1-3 Fibrillin-1 negatively regulates transforming growth factor (TGF)-␤, and the augmented TGF-␤/ Smad2-signaling in MFS contributes to the prominent clinical manifestations in the cardiovascular, ocular, skeletal, and pulmonary systems. 4 -7 Fibrillin-1 is a structural component of microfibrils, which are crucial in the formation, maturation, and stabilization of elastic fibers. Elastic fibers provide much of the physiological recoil of the aorta during systole. Abnormality in the formation and integrity of elastic fibers in MFS causes weakening of the aorta, making it vulnerable to dilatation and dissection. 3 Aortic rupture is the major cause of death in patients with MFS. If untreated, it significantly shortens the lifespan of affected individuals; half will succumb in their late 20s or early 30s. 8 ␤-Adrenoceptor blockade has been advocated as preventive therapy to decrease the rate of aortic root dilation and progression to dissection in patients with MFS. 9 ␤-Adrenoceptors are classified as ␤1 and ␤2, and atenolol is a selective ␤1 inhibitor, which effectively reduces contractility and slows the heart rate. Although ␤-blocker therapy is pres...

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