Spatiotemporal Multi-Omics Mapping Generates a Molecular Atlas of the Aortic Valve and Reveals Networks Driving Disease

作者：Florian Schlotter, Arda Halu, Shinji Goto, Mark C. Blaser, Simon C. Body, Lang Ho Lee, Hideyuki Higashi, Daniel M. DeLaughter, Joshua D. Hutcheson, Payal Vyas, Tan Pham, Maximillian A. Rogers, Amitabh Sharma, Christine E. Seidman, Joseph Loscalzo, Jonathan G. Seidman, Masanori Aikawa, Sasha A. Singh, Elena Aïkawa · 发表于：Circulation · 年份：2018 · DOI：10.1161/circulationaha.117.032291 · 被引用次数：260 · 研究领域：Cardiac Valve Diseases and Treatments、Aortic Disease and Treatment Approaches、Cardiac Fibrosis and Remodeling

BACKGROUND: No pharmacological therapy exists for calcific aortic valve disease (CAVD), which confers a dismal prognosis without invasive valve replacement. The search for therapeutics and early diagnostics is challenging because CAVD presents in multiple pathological stages. Moreover, it occurs in the context of a complex, multi-layered tissue architecture; a rich and abundant extracellular matrix phenotype; and a unique, highly plastic, and multipotent resident cell population. METHODS: A total of 25 human stenotic aortic valves obtained from valve replacement surgeries were analyzed by multiple modalities, including transcriptomics and global unlabeled and label-based tandem-mass-tagged proteomics. Segmentation of valves into disease stage-specific samples was guided by near-infrared molecular imaging, and anatomic layer-specificity was facilitated by laser capture microdissection. Side-specific cell cultures were subjected to multiple calcifying stimuli, and their calcification potential and basal/stimulated proteomes were evaluated. Molecular (protein-protein) interaction networks were built, and their central proteins and disease associations were identified. RESULTS: Global transcriptional and protein expression signatures differed between the nondiseased, fibrotic, and calcific stages of CAVD. Anatomic aortic valve microlayers exhibited unique proteome profiles that were maintained throughout disease progression and identified glial fibrillary acidic protein as a spec...