Aortic valve sclerosis is a highly prevalent, poorly characterized asymptomatic manifestation of calcific aortic valve disease and may represent a therapeutic target for disease mitigation. Human aortic valve cusps and blood were obtained from 333 patients undergoing cardiac surgery (n = 236 for severe aortic stenosis, n = 35 for asymptomatic aortic valve sclerosis, n = 62 for no valvular disease), and a multiplex assay was used to evaluate protein expression across the spectrum of calcific aortic valve disease. A subset of six valvular tissue samples (n = 3 for asymptomatic aortic valve sclerosis, n = 3 for severe aortic stenosis) was used to create RNA sequencing profiles, which were subsequently organized into clinically relevant gene modules. RNA sequencing identified 182 protein-encoding, differentially expressed genes in aortic valve sclerosis vs. aortic stenosis; 85% and 89% of expressed genes overlapped in aortic stenosis and aortic valve sclerosis, respectively, which decreased to 55% and 84% when we targeted highly expressed genes. Bioinformatic analyses identified six differentially expressed genes encoding key extracellular matrix regulators: TBHS2, SPARC, COL1A2, COL1A1, SPP1, and CTGF. Differential expression of key circulating biomarkers of extracellular matrix reorganization was observed in control vs. aortic valve sclerosis (osteopontin), control vs. aortic stenosis (osteoprotegerin), and aortic valve sclerosis vs. aortic stenosis groups (MMP-2), which corresponded to valvular mRNA expression. We demonstrate distinct mRNA and protein expression underlying aortic valve sclerosis and aortic stenosis. We anticipate that extracellular matrix regulators can serve as circulating biomarkers of early calcific aortic valve disease and as novel targets for early disease mitigation, pending prospective clinical investigations.

中文翻译：

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钙化性主动脉瓣疾病中的循环和组织基质细胞 RNA 和蛋白质表达。

主动脉瓣硬化是钙化性主动脉瓣疾病的一种高度流行、特征不佳的无症状表现，可能代表缓解疾病的治疗目标。从 333 名接受心脏手术的患者（严重主动脉瓣狭窄 n = 236，无症状主动脉瓣硬化 n = 35，无瓣膜疾病 n = 62）中获取人类主动脉瓣尖和血液，并使用多重检测评估蛋白质在钙化性主动脉瓣疾病谱中的表达。六个瓣膜组织样本的子集（无症状主动脉瓣硬化 n = 3，严重主动脉瓣狭窄 n = 3）用于创建 RNA 测序图谱，随后将其组织成临床相关的基因模块。RNA 测序鉴定了 182 种蛋白质编码，主动脉瓣硬化与主动脉狭窄的差异表达基因；85% 和 89% 的表达基因分别在主动脉瓣狭窄和主动脉瓣硬化中重叠，当我们针对高表达基因时，分别下降到 55% 和 84%。生物信息学分析确定了编码关键细胞外基质调节因子的六个差异表达基因：TBHS2、SPARC、COL1A2、COL1A1、SPP1 和 CTGF。在对照与主动脉瓣硬化（骨桥蛋白）、对照与主动脉狭窄（骨保护素）和主动脉瓣硬化与主动脉狭窄组 (MMP-2) 中观察到细胞外基质重组的关键循环生物标志物的差异表达，其对应于瓣膜 mRNA 表达。我们证明了主动脉瓣硬化和主动脉瓣狭窄的不同 mRNA 和蛋白质表达。