Beta-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 (0.24 g/L,
n=30), or given
atenolol (0.5 g/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-beta 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-beta activation.