Abstract
Aortic valve (AV) disease involves stiffening of the AV cusp with progression characterized by inflammation, fibrosis, and calcification. Here, we examine the relationship between biomechanical valve function and proteomic changes before and after the development of AV pathology in the Emilin1−/− mouse model of latent AV disease. Biomechanical studies were performed to quantify tissue stiffness at the macro (micropipette) and micro (atomic force microscopy (AFM)) levels. Micropipette studies showed that the Emilin1−/− AV annulus and cusp regions demonstrated increased stiffness only after the onset of AV disease. AFM studies showed that the Emilin1−/− cusp stiffens before the onset of AV disease and worsens with the onset of disease. Proteomes from AV cusps were investigated to identify protein functions, pathways, and interaction network alterations that occur with age- and genotype-related valve stiffening. Protein alterations due to Emilin1 deficiency, including changes in pathways and functions, preceded biomechanical aberrations, resulting in marked depletion of extracellular matrix (ECM) proteins interacting with TGFB1, including latent transforming growth factor beta 3 (LTBP3), fibulin 5 (FBLN5), and cartilage intermediate layer protein 1 (CILP1). This study identifies proteomic dysregulation is associated with biomechanical dysfunction as early pathogenic processes in the Emilin1−/− model of AV disease.
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Abbreviations
- AFM:
-
Atomic force microscopy
- AV:
-
Aortic valve
- ECM:
-
Extracellular matrix
- TGFB1:
-
Transforming growth factor beta 1
- VIC:
-
Valve interstitial cell
- WT:
-
Wild type
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Acknowledgments
We thank Aaron Reed for help in microscopy work and Susana Comte-Walters for help in proteomics data analysis. This study was supported by the National Center for Advancing Translational Sciences of the NIH (P.M.A., UL1 TR000445), National Institute of General Medical Sciences (P.M.A., P20 GM103542-06) the National Heart Lung and Blood Institute of the NIH (R.B.H., HL117851) an Institutional Clinical and Translational Science Award (R.B.H., NIH/NCRR 8UL1TR000077), and the Cincinnati Children’s Research Foundation (R.B.H.).
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Angel, P.M., Narmoneva, D.A., Sewell-Loftin, M.K. et al. Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease. Ann Biomed Eng 45, 2548–2562 (2017). https://doi.org/10.1007/s10439-017-1899-0
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DOI: https://doi.org/10.1007/s10439-017-1899-0