Abstract 4280: Combination of Doxycycline and Losartan is an Effective Secondary Prevention Treatment for the Thoracic Aortic Aneurysm in Marfan Syndrome

Abstract

Losartan, an antihypertensive drug, has been shown to prevent thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) through the inhibition of transforming growth factor (TGF)-β. Recently we have suggested doxycycline, a non-specific inhibitor of matrix metalloproteinases (MMPs), suppressed aneurysm and normalized vasomotor function in TA. We hypothesized that a combination of doxycycline and losartan could be effective in the secondary prevention to ameliorate TAA in MFS. A well-defined mouse model of Marfan syndrome (Fbn1 C1039G/+ ) were untreated (n=20), given doxycycline (0.24g/L, n=15), losartan (0.6g/L, n=15), or doxycycline+losartan (0.12g/L+0.3g/L, respectively, n=15) from drinking water at the age of 4 months. The littermate Fbn1 +/+ mice served as control (n=20). Ascending thoracic aortae from each group at 9 months were studied. Mortality (2%) and TAA (increase in diameter by >35%) were observed in the untreated group. Mild aneurysm (diameter of aorta was increased by 15% compared with controls) was evident in either losartan-or doxycycline-groups, but TAA was prevented by the combined treatment. From the aortic media of untreated, losartan- and doxcycline-groups, elastic fiber degeneration shown on Movat’s histology was pronounced, which accompanied with increased aortic stiffness. Combined treatment attenuated elastic fiber degradation and normalized the aortic elasticity to the control levels. The impairment of smooth muscle contraction and endothelial-dependent relaxation in the untreated group were also completely normalized by the combined treatment. Either losartan- or doxcycline-groups improved aortic contractility by 75% compared with the untreated, but was not effective in improving endothelium-dependent relaxation. Combined treatment reduced activities of MMP-2 and -9 in the aortic media by 60 – 80%, and activation of TGF-β by 70%. Delayed treatment reduced effectiveness of both losartan and doxycycline in the prevention of TAA. Combination of doxycycline and losartan is effective in the secondary prevention to preserve elastic fiber integrity and normalize vasomotor function, indicating that both MMP and TGF-β are crucial mediators in TAA formation in MFS.