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Transcriptional Profiling of Normal, Stenotic, and Regurgitant Human Aortic Valves

ABSTRACT: Purpose: The goal of this study is to characterize the gene expression profiles and identify genes of interest (GOI) in stenotic (AS) and regurgitant (AI) human aortic valves using RNA sequencing technology. Methods: Aortic valve leaflets were collected from non-matched transplant donor hearts (NC) and from aortic valve replacement operations (AS or AI). Leaflets were washed in cold PBS, snap frozen, and stored at -80°C until RNA extraction. For each sample, total RNA was extracted, a cDNA library was generated, and an Illumina HiSeq 2500 was used to sequence each sample. 150-bp paired-ends reads were generated with approximately 30 million reads per sample. Sequencing was performed in duplicate for each sample. Paired-end clean reads were aligned to the reference genome using STAR. HTSeq v0.6.1 was used to count the read numbers mapped to each gene. Fragments per kilobases per million (FPKM) were calculated to estimate the level of gene expression. Differential gene expression analysis was performed using the DESeq2 R package. A model based on the negative binomial distribution was used to determine differential gene expression (log 2 [fold change]). P-values were adjusted using the Benjamini-Hochberg approach for controlling false discovery rate. Genes with adjusted P-values <0.05 found by DESeq2 were assigned as differentially-expressed genes (DEGs). Results: RNA sequencing analysis identified 8,621 DEGs among the AS, AI, and NC valves. Specifically, 6,438 genes were found to be differentially expressed between the AS and NC groups; 4,994 genes were found to be differentially expressed between the AI and NC groups; and 2,771 genes were found to be differentially expressed between the AS and AI groups. Of these, 1,979 (31%) genes were expressed at statistically different levels between the AS and NC groups, and 1,428 (29%) genes were expressed at statistically different levels between the AI and NC groups Conclusions: Overall, we have sequenced aortic leaflets from non-matched transplant donor hearts , thereby establishing a new standard for normal aortic valve transcriptional profiling. We have also sequenced human aortic valves with AI and demonstrated that valves with AI and AS possess unique gene expression patterns. The plethora of DEGs identified and our novel PPI networks for AS and AI have revealed new pathways missed by previous aortic valve studies. Our data lays the foundation for future gene editing studies and may guide researchers in developing novel therapeutic interventions for AS and AI.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153555 | GEO | 2020/07/01

REPOSITORIES: GEO

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Project description:Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure. Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.

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Transcriptional Profiling of Normal, Stenotic, and Regurgitant Human Aortic Valves

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