Collagen fiber regulation in human pediatric aortic valve development and disease.
Collagen fiber regulation in human pediatric aortic valve development and disease.
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DOI：
10.1038/s41598-021-89164-w
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发表时间：
2021-05-07
影响因子：
4.6
通讯作者：
Angel PM
中科院分区：
文献类型：
--
作者：
Clift CL;Su YR;Bichell D;Jensen Smith HC;Bethard JR;Norris-Caneda K;Comte-Walters S;Ball LE;Hollingsworth MA;Mehta AS;Drake RR;Angel PM
先天性主动脉瓣狭窄(CAVS)影响高达10%的世界人口，没有药物治疗这种疾病。人们不断寻找新的分子靶标来阻止骑士队的进步。胶原蛋白去调控是骑士队的一个标志，但大多数情况下仍未明确。在这里，组织学研究与高分辨率准确质量(HRAM)胶原靶向蛋白质组学相结合，研究胶原调节的胶原纤维产生与人类房室发育和儿童终末期CAVS(PCAVS)相关。组织学研究证实了pCAVS中胶原纤维的重排和高密度胶原的独特区域。蛋白质组学分析报道，特定的胶原肽被羟化的脯氨酸(HYP)修饰，这是一种翻译后修饰，对稳定胶原三螺旋至关重要。定量数据分析报告了不同患者类别中胶原HYP位点的显著调节。已鉴定的非胶原型ECM蛋白(44个总蛋白中的26个)在胶原的合成、调节或修饰中具有直接的相互作用。网络分析确定Bambi(BMP和激活素膜结合抑制物)是胶原相互作用组的潜在上游调节因子。这是第一个详细说明胶原类型和HYP修饰与人房室发育和pCAVS相关的研究。我们预计，这项研究将为抑制PCAVS瓣膜退化的新的治疗途径和设计的瓣膜置换方案提供信息。
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.
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