Abstract 13843: Superoxide Dismutase 1 is a Critical Determinant of Pro-Fibrotic Signaling in Myxomatous Mitral Valve Disease
Myxomatous mitral valve disease (MMVD) is associated with valvular fibrosis and matrix remodeling, leading to leaflet prolapse and heart failure. Molecular mechanisms contributing to MMVD, however, remain poorly understood. We tested the hypotheses that increased reactive oxygen species are mediators of increased TGFβ signaling and resultant increases in pro-fibrotic and matrix remodeling gene expression in human and mouse mitral valves. We used qRT-PCR to measure expression of TGF-β1, matrix metalloproteinase (MMP) 2 and 9, connective tissue growth factor (CTGF), NAD(P)H oxidase catalytic subunits (Nox) 2 and 4, and superoxide dismutase (SOD) 1 in normal and myxomatous human mitral valves and also in mitral valves from wild-type and SOD1 knockout mice. We also used dihydroethidium (DHE) staining to measure levels of reactive oxygen species in tissue from human normal and myxomatous mitral valves. We found increased expression of TGF-β (163± 16%), CTGF (180± 25%), and MMP2 (248± 40%) but not MMP9 in human myxomatous mitral valves (n = 24). In addition we found that DHE fluorescence increased from 27± 3 relative fluorescent units (RFU) in normal valves to 36± 3 RFU in MMVD (p < 0.05). These increases were associated with enhanced Nox2 (228± 32%) and Nox4 (234± 55%) expression, despite increases in SOD1 (174± 30%). Profibrotic and matrix remodeling gene expression was also elevated in mitral valves of SOD1-deficient mice compared to wild-type littermates with increases in CTGF (133± 9%; p < 0.05) and MMP2 (128± 7%, p < 0.05), but not MMP9. Nox2 (152± 11%) and Nox4 (142± 11%) were also significantly upregulated in SOD1-deficient mice. In conclusion, these data demonstrate for the first time that reactive oxygen species are independent contributors to fibrosis and matrix remodeling in the myxomatous mitral valve. Combined inhibition of TGF-β signaling and oxidative stress may be a useful therapeutic intervention to arrest the progress of myxomatous mitral valve degeneration.
- © 2011 by American Heart Association, Inc.