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A novel long noncoding RNA SNHG3 promotes osteoblast differentiation through BMP2 upregulation in calcific aortic valve disease

ABSTRACT: The role of long noncoding RNAs (lncRNAs) in calcific aortic valve disease (CAVD) remains largely elusive. This study aims to report a novel therapeutic lncRNA, SNHG3, and elucidate its role in CAVD. Based on high-throughput transcriptomic sequencing of human aortic valves, SNHG3 is among the most highly expressed lncRNAs in CAVD. Furthermore, SNHG3 upregulation is verified in human calcified aortic valves, osteoblastic human aortic valve interstitial cells (hVICs), and aortic valve tissues in CAVD mice. Moreover, knockdown of SNHG3 with antisense oligonucleotide markedly ameliorates aortic valve calcification in high cholesterol diet-treated ApoE-/- mice, as evidenced by reduced calcium deposition in the aortic valve leaflets, improved echocardiographic parameters, and decreased osteogenic differentiation markers (RUNX2, osteopontin, and osteocalcin) in aortic valves. Consistent with these in vivo findings, SNHG3 overexpression aggravates the calcification of hVICs, while knockdown of SNHG3 alleviates the process of differential calcification. Transcriptomics sequencing, gene set enrichment analyses, RNA-pull down, RNA immunoprecipitation and chromatin immunoprecipitation-qPCR show that SNHG3 physically interacts with polycomb repressive complex 2 to suppress the H3K27 tri-methylation BMP2 locus, which in turn activates BMP2 expression and signaling pathways. Taken together, SNHG3 promotes aortic valve calcification by upregulating BMP2, which might be a novel therapeutic target in human CAVD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199718 | GEO | 2022/10/01

REPOSITORIES: GEO

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Project description:Aims Calcific aortic valve disease (CAVD) is a significant cause of illness and death worldwide. The disease mechanism involves age-associated immuno-osteogenic processes but developmental origins and early disease mechanisms are not fully characterized. Identification of early predictive markers could help optimize therapy decisions and patient follow-up. Methods and Results RNA-sequencing was carried out on human fetal aortic valves at weeks 9, 13, and 22, and adult control, calcified bicuspid (BAV) and tricuspid aortic valves (TAV). K-means clustering was implemented to identify co-expressed gene patterns simultaneously up- and down-regulated over the different conditions. Canonical pathway analysis revealed a predominant immune-metabolic gene signature indicative of ongoing innate and adaptive immune responses, including lymphocyte T-cell metabolic adaptation. Specifically, cytokine and chemokine signalling, cellular migration and proliferation, were all increased in CAVD, while oxidative phosphorylation and protein translation were decreased. Discrete immune-metabolic gene signatures were present at foetal stages and adult controls, indicating that inflammation initiates as soon as the valves are formed and is maintained and amplified during post-natal life. Multiple pathways involved in cellular stress response and neurodegenerative disease were also aberrantly expressed, suggesting that chronic inflammation drives metabolic stress- and age-associated valve pathology in CAVD. Comparing the valve RNA-sequencing dataset with whole blood transcriptomes from asymptomatic individuals with early aortic valve calcification identified a gene signature including the CD28 pathway, highly predictive of patients with CAVD and healthy individuals with moderate levels of aortic valve calcification. Conclusion These data deepen and broaden our understanding of the molecular basis of CAVD, and identify a gene signature for the early detection of aortic valve calcification. Keywords Human foetal valve, CAVD, BAV, inflammation, biomarker, gene signature,PESA

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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A novel long noncoding RNA SNHG3 promotes osteoblast differentiation through BMP2 upregulation in calcific aortic valve disease

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