| First Author | Hagler MA | Year | 2013 |
| Journal | Cardiovasc Res | Volume | 99 |
| Issue | 1 | Pages | 175-84 |
| PubMed ID | 23554457 | Mgi Jnum | J:211436 |
| Mgi Id | MGI:5575448 | Doi | 10.1093/cvr/cvt083 |
| Citation | Hagler MA, et al. (2013) TGF-beta signalling and reactive oxygen species drive fibrosis and matrix remodelling in myxomatous mitral valves. Cardiovasc Res 99(1):175-84 |
| abstractText | AIMS: Myxomatous mitral valve disease (MMVD) is associated with leaflet thickening, fibrosis, matrix remodelling, and leaflet prolapse. Molecular mechanisms contributing to MMVD, however, remain poorly understood. We tested the hypothesis that increased transforming growth factor-beta (TGF-beta) signalling and reactive oxygen species (ROS) are major contributors to pro-fibrotic gene expression in human and mouse mitral valves. METHODS AND RESULTS: Using qRT-PCR, we found that increased expression of TGF-beta1 in mitral valves from humans with MMVD (n = 24) was associated with increased expression of connective tissue growth factor (CTGF) and matrix metalloproteinase 2 (MMP2). Increased levels of phospho-SMAD2/3 (western blotting) and expression of SMAD-specific E3 ubiquitin-protein ligases (SMURF) 1 and 2 (qRT-PCR) suggested that TGF-beta1 signalling occurred through canonical signalling cascades. Oxidative stress (dihydroethidium staining) was increased in human MMVD tissue and associated with increases in NAD(P)H oxidase catalytic subunits (Nox) 2 and 4, occurring despite increases in superoxide dismutase 1 (SOD1). In mitral valves from SOD1-deficient mice, expression of CTGF, MMP2, Nox2, and Nox4 was significantly increased, suggesting that ROS can independently activate pro-fibrotic and matrix remodelling gene expression patterns. Furthermore, treatment of mouse mitral valve interstitial cells with cell permeable antioxidants attenuated TGF-beta1-induced pro-fibrotic and matrix remodelling gene expression in vitro. CONCLUSION: Activation of canonical TGF-beta signalling is a major contributor to fibrosis and matrix remodelling in MMVD, and is amplified by increases in oxidative stress. Treatments aimed at reducing TGF-beta activation and oxidative stress in early MMVD may slow progression of MMVD. |
