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.
Highlights
Valves during somatic growth[4]
Results of this study indicate that pediatric end-stage congenital aortic valve stenosis (pCAVS) shows fundamental differences in collagen fiber organization, collagen type regulation, and regulation of proline hydroxylation of collagens
Collagen from human aortic valve samples was studied across three patient categories: normal, pediatric end-stage congenital aortic valve stenosis, and aortic valve insufficiency (AVI) (Table 1)
Summary
Valves during somatic growth[4]. There is an ongoing need for identifying therapeutic targets, for the pediatric population. Collagen deregulation is a hallmark of adult and pediatric valvular stenosis[5,17,18] and a potential prognostic and therapeutic t arget[19,20], very little is known about the complexities of collagen fiber regulation in the human valve. Results of this study indicate that pCAVS shows fundamental differences in collagen fiber organization, collagen type regulation, and regulation of proline hydroxylation of collagens. These studies are the first to report specific collagen regulation due to pCAVS, and establish a foundation for new translational and post-translational collagen studies in fibrotic cardiovascular disease
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