Perspectives on pediatric congenital aortic valve stenosis: Extracellular matrix proteins, post translational modifications, and proteomic strategies

Figures

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  FIGURE 1. Flowchart displaying distribution of extracellular matrix proteins during the stages of valve development, from early embryonic through the mature aortic valve. GAG, glycosaminoglyca; SHF, second heart field; CNCC, cardiac neural crest cells; EndMT, endothelial to mesenchymal transition; VIC, valvular interstitial cells [development information edited from Combs et al. (6). ECM information edited from Peacock et al. (4)].

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  FIGURE 2. In silico post-translational modification (PTM) site frequency analysis of valvular structural proteins (collagens and elastin); uniport reporting. Glyc, glycosylation; HYP, hydroxyproline; HYL, hydroxylysine; Phospho, phosphorylation.

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  FIGURE 3. Comparative summary of transcriptomic and proteomic profiles of pediatric bicuspid aortic valve disease and adult fibrocalcific CAVS. Extracellular matrix (ECM) signatures (left), post-translational modifications or related enzymes (middle) and non-ECM/PTM signatures (right) are shown. All signatures are described as global changes unless otherwise specified (F, fibrosa; S, spongiosa; V, ventricularis). For the purposes of this review, the top layer-specific alteration is shown. FN1, fibronectin; BGH3, TGFB induced protein ig-h3; MEF2C, myocycte-specific enhancer factor 2C; TWIST1, twist-related protein 1; MSX2, homobox protein MSX2. VWF, Von Willebrand Factor; VTN, vitronectin; NID1, nidogen-1; P4H1, prolyl-4 hydroxylase-1; LOX, lipoxygenase; H3,H4, histone3,4; USP9X, ubiquitin carboxyl-terminal hydrolase FAF-X; Runx2, runt-related transcription factor-2; ITH4, inter-alpha trypsin inhibitor heavy chain 4; CPA3, carboxypeptidase A3; TPM2, tropomyosin 2. Figure created using BioRender.com (2022).

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  FIGURE 4. Current treatment options, bioengineered solutions, and the Ross Procedure. (A) Potential aortic valve intervention strategies in pediatric patients, adapted from Bouhout et al. (91). (B) Schematic drawing of the Ross procedure, which switches the native pulmonary valve into the aortic position. Figure created using BioRender.com (2022).

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  FIGURE 5. Graphical summary of technological advancements to be applied to pCAVS. Unbiased approaches, such as proteomics and transcriptomics, allow for novel discovery of disease markers. Advancements in acquisition techniques as described allow for a deeper mining of the extracellular matrisome, previously limited in accessibility. This increased accessibility allows for identification of post-translational modifications; while multi-omics integration probe upstream regulating enzymes, accelerating identification of therapeutic targets. Extracellular matrix targeted -omics techniques have the potential to elucidate fibrosis-specific biomarkers, highlighting the distinct molecular mechanisms between adult calcific and pediatric fibrotic CAVS. Graphics created using BioRender.com (2022).