Spatial N-glycomics of the human aortic valve in development and pediatric endstage congenital aortic valve stenosis.
Spatial N-glycomics of the human aortic valve in development and pediatric endstage congenital aortic valve stenosis.
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DOI：
10.1016/j.yjmcc.2021.01.001
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发表时间：
2021-05
影响因子：
5
通讯作者：
Su YR
中科院分区：
文献类型：
--
作者：
Angel PM;Drake RR;Park Y;Clift CL;West C;Berkhiser S;Hardiman G;Mehta AS;Bichell DP;Su YR
先天性主动脉瓣狭窄(AS)是由于主动脉瓣(AV)叶细胞外基质(ECM)分泌失调而导致的主动脉口梗阻性狭窄，导致心力衰竭，目前尚无有效的治疗方法。糖蛋白和蛋白多糖分布的改变是AS的一个标志，然而瓣膜碳水化合物含量在分子水平上仍然没有明确的特征。虽然几乎所有临床上与瓣膜狭窄模型相关的糖蛋白都含有多个N-糖基化位点，但很少有报道旨在了解N-糖基化如何在疾病中对瓣膜结构起作用。在这里，我们测试了N-糖链结构在儿童先天性主动脉瓣狭窄中的空间定位。这项研究是在0-17岁的瓣膜组织上进行的，临床数据显示，术前瓣膜功能包括正常发育、主动脉瓣关闭不全(AVI)和儿童终末期AS。高质量精度成像质谱仪(IMS)用于定位房室结构中的N-葡聚糖图谱。RNA-Seq用于鉴定N-糖链相关酶的调控。N-糖蛋白定位于正常的主动脉瓣内，与纤维膜、海绵膜或室壁排列一致。在AVI诊断的组织中，N-葡聚糖定位于肥大的连合，并增加了稀疏甘露糖结构。在所有瓣膜类型中，唾液酸(N-乙酰神经氨酸)N-糖基是最丰富的N-糖基。3个唾液酸化的N-糖链在AS中表现出共同的升高，与年龄无关。为瓣膜组织优化的组织上化学方法确定，主动脉瓣组织唾液酸化显示α2，6和α2，3连接。专门的酶策略表明，核心岩藻糖基化是岩藻糖的主要构型，并定位于正常纤维组织，在AS中具有不同的模式。本研究证实人主动脉瓣结构是由N-葡萄糖信号在空间上定义的，并可能为人类主动脉瓣疾病的治疗提供新的研究方向。
Congenital aortic valve stenosis (AS) progresses as an obstructive narrowing of the aortic orifice due to deregulated extracellular matrix (ECM) production by aortic valve (AV) leaflets and leads to heart failure with no effective therapies. Changes in glycoprotein and proteoglycan distribution are a hallmark of AS, yet valvular carbohydrate content remains virtually uncharacterized at the molecular level. While almost all glycoproteins clinically linked to stenotic valvular modeling contain multiple sites for N-glycosylation, there are very few reports aimed at understanding how N-glycosylation contributes to the valve structure in disease. Here, we tested for spatial localization of N-glycan structures within pediatric congenital aortic valve stenosis. The study was done on valvular tissues 0–17 years of age with de-identified clinical data reporting pre-operative valve function spanning normal development, aortic valve insufficiency (AVI), and pediatric endstage AS. High mass accuracy imaging mass spectrometry (IMS) was used to localize N-glycan profiles in the AV structure. RNA-Seq was used to identify regulation of N-glycan related enzymes. The N-glycome was found to be spatially localized in the normal aortic valve, aligning with fibrosa, spongiosa or ventricularis. In AVI diagnosed tissue, N-glycans localized to hypertrophic commissures with increases in pauci-mannose structures. In all valve types, sialic acid (N-acetylneuraminic acid) N-glycans were the most abundant N-glycan group. Three sialylated N-glycans showed common elevation in AS independent of age. On-tissue chemical methods optimized for valvular tissue determined that aortic valve tissue sialylation shows both α2,6 and α2,3 linkages. Specialized enzymatic strategies demonstrated that core fucosylation is the primary fucose configuration and localizes to the normal fibrosa with disparate patterning in AS. This study identifies that the human aortic valve structure is spatially defined by N-glycomic signaling and may generate new research directions for the treatment of human aortic valve disease.
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影响因子：
2.7
作者：
Dupuis LE;McCulloch DR;McGarity JD;Bahan A;Wessels A;Weber D;Diminich AM;Nelson CM;Apte SS;Kern CB
通讯作者：
Kern CB
DOI：
10.1007/978-1-4939-2343-4_1
发表时间：
2015-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Damerell, David;Ceroni, Alessio;Haslam, Stuart M
通讯作者：
Haslam, Stuart M
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.4
作者：
Angel, Peggi M.;Comte-Walters, Susana;Drakes, Richard R.
通讯作者：
Drakes, Richard R.
DOI：
10.1161/01.atv.0000106321.63667.24
发表时间：
2004-01-01
影响因子：
8.7
作者：
Chiu, JJ;Lee, PL;Chien, S
通讯作者：
Chien, S