Collagen fiber regulation in human pediatric aortic valve development and disease

Abstract

Congenital aortic valve stenosis (CAVS) affects up to 10% of the world population without medical therapies to treat the disease. New molecular targets are continually being sought that can halt CAVS progression. Collagen deregulation is a hallmark of CAVS yet remains mostly undefined. Here, histological studies were paired with high resolution accurate mass (HRAM) collagen-targeting proteomics to investigate collagen fiber production with collagen regulation associated with human AV development and pediatric end-stage CAVS (pCAVS). Histological studies identified collagen fiber realignment and unique regions of high-density collagen in pCAVS. Proteomic analysis reported specific collagen peptides are modified by hydroxylated prolines (HYP), a post-translational modification critical to stabilizing the collagen triple helix. Quantitative data analysis reported significant regulation of collagen HYP sites across patient categories. Non-collagen type ECM proteins identified (26 of the 44 total proteins) have direct interactions in collagen synthesis, regulation, or modification. Network analysis identified BAMBI (BMP and Activin Membrane Bound Inhibitor) as a potential upstream regulator of the collagen interactome. This is the first study to detail the collagen types and HYP modifications associated with human AV development and pCAVS. We anticipate that this study will inform new therapeutic avenues that inhibit valvular degradation in pCAVS and engineered options for valve replacement.

Jinlian Xiaodu Decoction Protects against Bleomycin-Induced Pulmonary Fibrosis in Rats

“…In addition, JXD alleviated BLM-induced oxidative stress by decreasing the content of NO as well as increasing the activity of GSH, SOD, thus reducing MDA content. Importantly, JXD decreased the level of HYP, which is a unique component of collagen fiber [ 37 ]. Thus, it was likely that JXD treatment suppressed cell apoptosis, attenuates oxidative stress, and fibroproliferation during the progress of PF in BLM-induced rats.…”

Defining the Tumor Microenvironment by Integration of Immunohistochemistry and Extracellular Matrix Targeted Imaging Mass Spectrometry

“…Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) can be utilized to generate both spatial and quantitative analysis of the vast variety of ECM proteins found on tissue [34][35][36]45,46]. In addition to obtaining map localization of proteins with respect to specific cells and the tumor, this imaging modality can also report putatively identified posttranslational modifications of these proteins [35,36,43,[45][46][47]. The developed workflow used in this study was aimed to investigate proteomic acquired stromal analysis of formerly immunohistochemistry stained breast and hepatocellular carcinoma tissue with markers FAP, αSMA, P4HA3 and PTEN.…”

“…Tissue was prepared as previously with minor modifications [34,35,43,44]. Previously stained tissues were incubated in xylene for 24-72 h to remove coverslips.…”

Connections for Matters of the Heart: Network Medicine in Cardiovascular Diseases

“…Sun et al used centrality measures to compare various disease categories, providing novel ways to evaluate potential drug targets ( 96 ). Other applications of nodes’ topological properties to CVDs include heart failure ( 97 ), calcified aortic valve disease (CAVD) ( 98 , 99 ), rheumatic heart valve disease ( 100 ), and ischemic stroke ( 101 ). Like network properties of individual genes, leveraging pathways’ properties can glean the hierarchical structure of disease organization.…”