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

• DOI: 10.1161/circulationaha.117.032291
• Publication Date: 2018-03-27T09:25:13Z
• Authors: Florian Schlotter; Arda Halu; Shinji Goto; Mark C. Blaser; Simon C. Body; Lang H. Lee; Hideyuki Higashi; Daniel M. DeLaughter; Joshua D. Hutcheson; Payal Vyas; Tan Pham; Maximillian A. Ro...; Amitabh Sharma; Christine E. Seidman; Joseph Loscalzo; Jonathan G. Seidman; Masanori Aikawa; Sasha A. Singh; Elena Aikawa
• Keywords: Proteome; Osteonectin; Laser capture microdissection

Background: No pharmacological therapy exists for calcific aortic valve disease (CAVD), which confers a dismal prognosis without invasive replacement. The search therapeutics and early diagnostics is challenging because CAVD presents in multiple pathological stages. Moreover, it occurs the context of complex, multi-layered tissue architecture; rich abundant extracellular matrix phenotype; unique, highly plastic, multipotent resident cell population. Methods: A total 25 human stenotic valves obtained from replacement surgeries were analyzed by modalities, including transcriptomics global unlabeled label-based tandem-mass-tagged proteomics. Segmentation into stage–specific samples was guided near-infrared molecular imaging, anatomic layer-specificity facilitated laser capture microdissection. Side-specific cultures subjected to calcifying stimuli, their calcification potential basal/stimulated proteomes evaluated. Molecular (protein–protein) interaction networks built, central proteins associations identified. Results: Global transcriptional protein expression signatures differed between nondiseased, fibrotic, stages CAVD. Anatomic microlayers exhibited unique proteome profiles that maintained throughout progression identified glial fibrillary acidic as specific marker valvular interstitial cells spongiosa layer. marked an emergence smooth muscle activation, inflammation, calcification-related pathways. Proteins overrepresented disease-prone fibrosa are functionally annotated fibrosis pathways, we found vitro, fibrosa-derived demonstrated greater than those ventricularis. These studies confirmed microlayer-specific preserved cultured cells, exposed alkaline phosphatase–dependent phosphatase–independent stimuli had distinct profiles, both overlapped with whole tissue. Analysis protein–protein significant closeness inflammatory fibrotic diseases. Conclusions: spatially temporally resolved multi-omics, network systems biology strategy identifies first regulatory CAVD, cardiac condition cure, describes novel means systematic ontology broadly applicable comprehensive omics cardiovascular