Dataset Information

Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection.

ABSTRACT: Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair.

SUBMITTER: Cikach FS

PROVIDER: S-EPMC5922288 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection.

Cikach Frank S FS Koch Christopher D CD Mead Timothy J TJ Galatioto Josephine J Willard Belinda B BB Emerton Kelly B KB Eagleton Matthew J MJ Blackstone Eugene H EH Ramirez Francesco F Roselli Eric E EE Apte Suneel S SS

JCI insight 20180308 5

Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial ...[more]

PMID: 29515038

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Project description:Background: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular event characterized by high mortality rates. Previous studies have shown that matrix metalloproteinases 19 (MMP19) was involved in TAAD formation, while the detailed role of MMP19 in TAAD pathogenesis and underlying mechanism remain unclear. Methods: To investigate the role of MMP19 in the progression of TAAD, we generated global Mmp19 knockout mice, as well as VSMCs (vascular smooth muscle cells)-specific Mmp19 knockdown mice, and established a BAPN-induced TAAD model. To elucidate the signaling pathways modulated by Aggrecan, we employed an adeno-associated virus serotype 9 (AAV9) vector encoding Acan short hairpin RNA (shRNA) for VSMC-specific knockdown of Acan. Ultimately, we injected an AAV vector encoding VSMC-specific Mmp19 into BAPN-induced TAAD mice to assess whether MMP19 can mitigate the development of TAAD. Results: Our findings revealed elevated mRNA and protein levels of MMP19 in the aortas of both TAAD mice and patients. The systemic ablation of Mmp19, as well as VSMC-specific Mmp19 knockdown, significantly exacerbated BAPN-induced progressive TAAD, and TAAD-related cardiovascular remodeling. Mmp19 deficiency resulted in the accumulation of Acan, but not Vcan, within the aorta, driving the phenotypic switch of VSMCs from contractile to synthetic state through activting Wnt/β-catenin signaling pathway. The selective inhibitor of Wnt/β-catenin signaling, MASB, was effective in reversing the dedifferentiation of VSMCs induced by aggrecan accumulation. Notably, the specific knockdown of Acan in VSMCs restored the contractile phenotype of VSMCs and inhibited Wnt/β-catenin signaling, thereby alleviating BAPN-induced TAAD in Mmp19-/- mice. Additionally, VSMC-specific complementation of MMP19 also alleviated the progressive TAAD phenotype in Mmp19-/- mice. Conclusions: The study underscores that MMP19 deficiency exacerbates TAAD by promoting Acan aggregation and destroying the homeostasis of VSMCs by activating Wnt/β-catenin signaling pathway. These results posit MMP19 as a promising novel therapeutic target for TAAD intervention.

Project description:BackgroundThoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events.ObjectivesThe purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework.MethodsWe applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel.ResultsGenes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD.ConclusionsThe ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.

Project description:ObjectiveThoracic aortic aneurysm and dissection (TAAD) is a cardiovascular disease with a high mortality rate. Aging is an important risk factor for TAAD. This study explored the relationship between aging and TAAD and investigated the underlying mechanisms, which may contribute to the diagnosis and treatment of TAAD.MethodsHuman aging genes were obtained from the Aging Atlas official website. Various datasets were downloaded from the GEO database:the human TAAD dataset GSE52093 were used for screening differentially expressed genes (DEGs); GSE137869, GSE102397 and GSE153434 were used as validation sets, and GSE9106 was used for diagnostic prediction of receiver operating characteristic (ROC) curves. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction (PPI) network analysis were used to screen differentially co-expressed genes from human aging genes and TAAD. Using five methods of the cytoHubba plugin in Cytoscape software (Degree, Closeness, EPC, MNC, Radiality), hub genes were identified from the differentially co-expressed genes. Single-cell RNA sequencing was used to verify the expression levels of hubgenes in different cell types of aortic tissue. ROC curves were used to further screen for diagnostic genes.ResultsA total of 70 differentially co-expressed genes were screened from human aging genes and DEGs in human TAAD dataset GSE52093. GO enrichment analysis revealed that the DEGs played a major role in regulating DNA metabolism and damaged DNA binding. KEGG enrichment analysis revealed enrichment in the longevity regulating pathway, cellular senescence, and HIF-1 signaling pathway. GSEA indicated that the DEGs were concentrated in the cell cycle and aging-related p53 signaling pathway. The five identified hubgenes were MYC, IL6, HIF1A, ESR1, and PTGS2. Single-cell sequencing of the aging rat aorta showed that hubgenes were expressed differently in different types of cells in aortic tissue. Among these five hubgenes, HIF1A and PTGS2 were validated in the aging dataset GSE102397; MYC, HIF1A and ESR1 were validated in the TAAD dataset GSE153434. The combined area under the diagnostic ROC curve (AUC) values for the five hub genes were >0.7 in the testing and training sets of the dataset GSE9106. The combined AUC values of MYC and ESR1 were equal to the combin ed AUC values of the five hub genes.ConclusionThe HIF-1 signaling pathway may play an important role in TAAD and aging. MYC and ESR1 may have diagnostic value for aging-related TAAD.

Dataset Information

Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection.

Publications

Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection.

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