Padang Ratnasari, Bagnall Richard D, Tsoutsman Tatiana, Bannon Paul G, Semsarian Christopher
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia; Baird Institute, Sydney, Australia; and.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia;
Physiol Genomics. 2015 Mar;47(3):75-87. doi: 10.1152/physiolgenomics.00115.2014. Epub 2014 Dec 29.
Intrinsic valvular degeneration and dysfunction is the most common complication of bicuspid aortic valve (BAV) disease. Phenotypically, it ranges from calcific aortic stenosis to redundant or prolapsing regurgitant leaflets. The underlying molecular mechanism underpinning phenotype heterogeneity of valvular degeneration in BAV is poorly understood. We used RNA sequencing (RNA-seq) to identify genes and pathways responsible for the development of valvular degeneration in BAV, compared with tricuspid aortic valve (TAV). Comparative transcriptome analysis was performed on total RNA of aortic valve tissues of patients with diseased BAV (n = 5) and calcified TAV (n = 3). RNA-seq findings were validated by RT-qPCR. A total of 59 and 177 genes were significantly up- and downregulated, respectively, in BAV compared with TAV. Hierarchical clustering indicated heterogeneity within the BAV group, separating those with heavy calcification (BAVc) from those with redundant leaflets and/or minimal calcification (BAVr). Interestingly, the gene expression profile of the BAVc group closely resembled the TAV, with shared up- and downregulation of inflammatory and NOTCH1 signaling pathways, respectively. Downregulation of matrix protease ADAMTS9 and protein aggrecan were observed in BAVr compared with TAV. Dysregulation of fetal gene programs were also present, with notable downregulation of SEMA6B and SEMA3F in BAVr and BAVc compared with TAV, respectively. Upregulation of TBX20 was observed exclusively in BAVr compared with BAVc. In conclusion, diverging molecular mechanisms underpin phenotype heterogeneity of valvular degeneration in BAV and data from the present study suggest that there may be shared mechanisms leading to calcification in BAV and TAV. Recognition of these pathways is fundamental to improve our understanding of the molecular basis of human BAV disease.
先天性瓣膜退变和功能障碍是二叶式主动脉瓣（BAV）疾病最常见的并发症。从表型上看，其范围从钙化性主动脉瓣狭窄到瓣叶冗长或脱垂伴反流。BAV中瓣膜退变表型异质性的潜在分子机制尚不清楚。我们使用RNA测序（RNA-seq）来识别与三尖瓣主动脉瓣（TAV）相比，导致BAV瓣膜退变的基因和信号通路。对患有BAV疾病的患者（n = 5）和钙化性TAV患者（n = 3）的主动脉瓣组织总RNA进行了比较转录组分析。RNA-seq结果通过RT-qPCR进行验证。与TAV相比，BAV中共有59个基因显著上调，177个基因显著下调。层次聚类表明BAV组内存在异质性，将重度钙化患者（BAVc）与瓣叶冗长和/或轻度钙化患者（BAVr）区分开来。有趣的是，BAVc组的基因表达谱与TAV非常相似，分别在炎症和NOTCH1信号通路中存在共同的上调和下调。与TAV相比，BAVr中基质蛋白酶ADAMTS9和蛋白聚糖下调。胎儿基因程序也存在失调，与TAV相比，SEMA6B和SEMA3F在BAVr和BAVc中分别显著下调。与BAVc相比，仅在BAVr中观察到TBX20上调。总之，不同的分子机制支撑了BAV中瓣膜退变的表型异质性，本研究数据表明BAV和TAV中可能存在导致钙化的共同机制。认识这些信号通路对于提高我们对人类BAV疾病分子基础的理解至关重要。
