Development Of Aortic Dissection Research Articles

Progress and perspectives of metabolic biomarkers in human aortic dissection.

Aortic dissection (AD) significantly threated human cardiovascular health, extensive clinical-scientific research programs have been executed to uncover the pathogenesis and prevention. Unfortunately, no specific biomarker was identified for the causality or development of human AD. Metabolomics, a high-throughput technique capable of quantitatively detecting metabolites, holds considerable promise in discovering specific biomarkers and unraveling the underlying pathways involved. Aiming to provide a metabolite prediction in human AD, we collected the metabolomics data from 2003 to 2023, and diligently scrutinized with the online system MetaboAnalyst 6.0. Based on the data obtained, we have concluded the metabolic dynamics were highly correlated with human AD. Such metabolites (choline, serine and uridine) were frequently involved in the AD. Besides, the pathways, including amino acids metabolism and lipids metabolism, were also dysregulated in the disease. Due to the current limitation of metabolism analysis, the integrative omics data including genomics, transcriptomics, and proteomics were required for developing the specific biomarker for AD.

LILRB4 knockdown inhibits aortic dissection development by regulating pyroptosis and the JAK2/STAT3 signaling pathway

Aortic dissection (AD) is a life-threatening condition with a high mortality rate and without effective pharmacological therapies. Our previous study illustrated that leukocyte immunoglobulin-like receptor B4 (LILRB4) knockdown promoted the contractile phenotypic switch and apoptosis of AD cells. This study aimed to further investigate the role of LILRB4 in animal models of AD and elucidate its underlying molecular mechanisms. Animal models of AD were established using 0.1% beta-aminopropionitrile and angiotensin II and an in vitro model was developed using platelet-derived growth factor BB (PDGF-BB). The effects of LILRB4 knockdown on histopathological changes, pyroptosis, phenotype transition, extracellular matrix (ECM), and Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) pathways were assessed using a series of in vivo and in vitro assays. The effects of the JAK2 inhibitor AG490 on AD cell function, phenotypic transition, and ECM were explored. LILRB4 was highly expressed in AD and its knockdown increased survival rate, reduced AD incidence, and alleviated histopathological changes in the AD mouse model. Furthermore, LILRB4 knockdown promoted contractile phenotype switch, stabilized the ECM, and inhibited pyroptosis. Mechanistically, LILRB4 knockdown inhibited the JAK2/STAT3 signaling pathway. JAK2 inhibitor AG490 inhibited cell viability and migration, enhanced apoptosis, induced G0/G1 cell cycle arrest, and suppressed S-phase progression in PDGF-BB-stimulated human aortic smooth muscle cells. LILRB4 knockdown suppresses AD development by inhibiting pyroptosis and the JAK2/STAT3 signaling pathway.

MiR-485-3p targets SIRT1 in vascular smooth muscle cells mediating the occurrence of aortic dissection.

Studies have demonstrated a close correlation between MicroRNA and the occurrence of aortic dissection (AD). However, the molecular mechanisms underlying this relationship have not been fully elucidated and further exploration is still required. In this study, we found that miR-485-3p was significantly upregulated in human aortic dissection tissues. Meanwhile, we constructed invitro AD models in HAVSMCs, HAECs and HAFs and found that the expression of miR-485-3p was increased only in HAVSMCs. Overexpression or knockdown of miR-485-3p in HAVSMCs could regulate the expression of inflammatory cytokines IL1β, IL6, TNF-α, and NLRP3, as well as the expression of apoptosis-related proteins BAX/BCL2 and Cleaved caspase3/Caspase3. In the invivo AD model, we have observed that miR-485-3p regulates vascular inflammation and apoptosis, thereby participating in the modulation of AD development in mice. Based on target gene prediction, we have validated that SIRT1 is a downstream target gene of miR-485-3p. Furthermore, by administering SIRT1 agonists and inhibitors to mice, we observed that the activation of SIRT1 alleviates vascular inflammation and apoptosis, subsequently reducing the incidence of AD. Additionally, functional reversal experiments revealed that overexpression of SIRT1 in HAVSMCs could reverse the cell inflammation and apoptosis mediated by miR-485-3p. Therefore, our research suggests that miR-485-3p can aggravate inflammation and apoptosis in vascular smooth muscle cells by suppressing the expression of SIRT1, thereby promoting the progression of aortic dissection.

Transketolase drives the development of aortic dissection by impairing mitochondrial bioenergetics.

Aortic dissection (AD) is a disease with rapid onset but with no effective therapeutic drugs yet. Previous studies have suggested that glucose metabolism plays a critical role in the progression of AD. Transketolase (TKT) is an essential bridge between glycolysis and the pentose phosphate pathway. However, its role in the development of AD has not yet been elucidated. In this study, we aimed to explore the role of TKT in AD. We collected AD patients' aortic tissues and used high-throughput proteome sequencing to analyze the main factors influencing AD development. We generated an AD model using BAPN in combination with angiotensin II (Ang II) and pharmacological inhibitors to reduce TKT expression. The effects of TKT and its downstream mediators on AD were elucidated using human aortic vascular smooth muscle cells (HAVSMCs). We found that glucose metabolism plays an important role in the development of AD and that TKT is upregulated in patients with AD. Western blot and immunohistochemistry confirmed that TKT expression was upregulated in mice with AD. Reduced TKT expression attenuated AD incidence and mortality, maintained the structural integrity of the aorta, aligned elastic fibers, and reduced collagen deposition. Mechanistically, TKT was positively associated with impaired mitochondrial bioenergetics by upregulating AKT/MDM2 expression, ultimately contributing to NDUFS1 downregulation. Our results provide new insights into the role of TKT in mitochondrial bioenergetics and AD progression. These findings provide new intervention options for the treatment of AD.

Gut microbial metabolite trimethylamine N-oxide induces aortic dissection

Aortic dissection (AD) is the most catastrophic vascular disease with a high mortality rate. Trimethylamine N-oxide (TMAO), a gut microbial metabolite, has been implicated in the pathogenesis of cardiovascular diseases. However, the role of TMAO in AD and the underlying mechanisms remain unclear. This study aimed to explore the effects of TMAO on AD. Plasma and fecal samples from patients with AD and healthy individuals were collected to analyze TMAO levels and gut microbial species, respectively. The plasma levels of TMAO were significantly higher in 253 AD patients compared with those in 98 healthy subjects (3.47, interquartile range (IQR): 2.33 to 5.18 μM vs. 1.85, IQR: 1.40 to 3.35 μM; p < 0.001). High plasma TMAO levels were positively associated with AD severity. An increase in the relative abundance of TMA-producing genera in patients with AD was revealed using 16S rRNA sequencing. In the angiotensin II or β-aminopropionitrile-induced rodent model of AD, mice fed a TMAO-supplemented diet were more likely to develop AD compared to mice fed a normal diet. Conversely, TMAO depletion mitigated AD formation in the BAPN model. RNA sequencing of aortic endothelial cells isolated from mice administered TMAO revealed significant upregulation of genes involved in inflammatory pathways. The in vitro experiments verified that TMAO promotes endothelial dysfunction and activates nuclear factor (NF)-κB signaling. The in vivo BAPN-induced AD model confirmed that TMAO increased aortic inflammation. Our study demonstrates that the gut microbial metabolite TMAO aggravates the development of AD at least in part by inducing endothelial dysfunction and inflammation. This study provides new insights into the etiology of AD and ideas for its management.

A proteome-wide screen identifies the calcium binding proteins, S100A8/S100A9, as clinically relevant therapeutic targets in aortic dissection

Aortic dissection (AD) is a fatal cardiovascular disease with limited pharmacotherapies. To discover novel therapeutic targets for AD, the present study was conducted on ascending aorta samples from AD patients versus those from control subjects using proteomic analysis. Integrated proteomic data analysis identified S100 calcium-binding proteins A8 and A9 (S100A8/A9) as new therapeutic targets for AD. As assessed by ELISA, the circulating levels of S100A8/A9 were elevated in AD patients. In addition, we validated the upregulation of S100A8/A9 in a mouse model of AD. In vitro and in vivo studies substantiated that S100A8/A9, as danger-associated molecular pattern molecules, promotes the smooth muscle cells phenotypic switch by inhibiting serum response factor (SRF) activity but elevating NF-κB dependent inflammatory response. Depletion of S100A8/A9 attenuates the occurrence and development of AD. As a proof of concept, we tested the safety and efficacy of pharmacological inhibition of S100A8/A9 by ABR-25757 (paquinimod) in a mouse model of AD. We observed that ABR-25757 ameliorated the incidence of rupture and improved elastin morphology associated with AD. Further single-cell RNA sequencing disclosed that the phenotypic switch of vascular smooth muscle cells (VSMCs) and inflammatory response pathways were responsible for ABR-25757-mediated protection against AD. Thus, this study reveals the regulatory mechanism of S100A8/A9 in AD and offers a potential therapeutic avenue to treat AD by targeting S100A8/A9.

Delamination Strength and Elastin Interlaminar Fibers Decrease with the Development of Aortic Dissection in Model Rats.

Aortic dissection (AD) is a life-threatening tear of the vascular tissue with creation of a false lumen. To explore the mechanism underlying this tissue tear, this study investigated the delamination strength of AD model rats and the histological composition of the aorta at various stages of AD development. SD rats were administrated beta-amino propionitrile for 0 (Control), 3 (Pre-dissection), and 6 (Dissection) weeks. The thoracic aorta was harvested at 10-11 weeks of age. The Dissection group exclusively showed AD at the ascending aorta. The delamination strength, a force that separates the aorta in the radial direction, of the descending aorta decreased significantly in the order of the Control, Pre-dissection, and Dissection groups. A quantitative histological analysis of the aortic tissue demonstrated that, compared with the Control group, the area fraction of collagen was significantly higher in the Pre-dissection and Dissection groups and that of elastin was significantly lower in the Dissection group. The area fraction of the elastin fibers between the elastic laminas (interlaminar fibers) was significantly decreased in the order of the Control, Pre-dissection, and Dissection groups. Histological changes of the aortic tissue, perhaps a reduction in interlaminar fibers mainly aligned in the radial direction, decreased delamination strength, thereby causing AD.

Abstract 13229: Coiled-Coil Domain-Containing Protein 80 Protects Against Aortic Dissection by Maintaining the Contractile Smooth Muscle Cell Phenotype

Background: Aortic dissection (AD) is a life-threatening medical emergency characterized by adverse vascular remodeling. Effective prevention and treatment options are lacking for AD. Coiled-coil domain-containing protein 80 (CCDC80) plays an essential role in regulating vascular remodeling. In the present study, we aimed to define the role of CCDC80 in the formation and development of AD. Methods: The expression and subcellular localization of CCDC80 were determined in human and mouse AD. CCDC80 knockout mice (CCDC80 –/– ) and vascular smooth muscle cell (VSMC)-specific CCDC80 knockout mice (CCDC80 fl/fl SM22α Cre + ) were treated with angiotensin II (Ang II) or Ang II combined with β-aminopropionitrile monofumarate (BAPN) to induce AD models. RNA-Seq analysis combined with immunoprecipitation and blockage of the JAK2/STAT3 signaling pathway in CCDC80 –/– mice were used to evaluate the effect of CCDC80 deficiency on this pathway. Results: CCDC80 was downregulated in VSMCs in human and mouse AD. CCDC80 – / – mice challenged with Ang II and BAPN developed AD with higher frequency and severity compared with their littermate controls (66.7% vs. 100%, p &lt; 0.05). Remarkably, compared with littermate controls treated with Ang II, CCDC80 –/– mice (8.3% vs. 87.5%, p &lt; 0.05) and CCDC80 fl/fl SM22α Cre + mice (12.5% vs. 80%, p &lt; 0.05) frequently developed AD with severe elastin fragmentation and collagen deposition. CCDC80 interacted with JAK2; CCDC80 deficiency could promote VSMC phenotype switching, proliferation, and migration as well as matrix metalloproteinase production by activating the JAK2/STAT3 signaling pathway. The JAK2/STAT3 pathway-specific inhibitor ameliorated adverse vascular remodeling and reduced AD formation (90% vs. 55%, p &lt; 0.05) in CCDC80 knockout mice. Conclusion: CCDC80 deficiency exacerbates the progression of AD by activating the JAK2/STAT3 pathway involved in regulating the phenotype switching and function of VSMCs. Our findings suggest that CCDC80 is a potential target for the prevention and treatment of AD.

Abstract 13284: New Elastic Fiber Formation by Non-Smooth Muscle Lineage Cells During the Progression of Aortic Dissections

Introduction: Aortic dissection (AD) is a life-threatening vascular disease displaying the disruption of the extracellular matrix (ECM). Elastic fibers are a major component of ECM and confer structural integrity to the aortic wall. Normally, elastic fibers are minimally synthesized in adulthood. However, it remains unknown whether and how elastic fibers are synthesized following ADs. Methods and Results: AD was induced by administration of β-aminopropionitrile (BAPN, 0.5% wt/vol) to male C57BL/6J mice at 4 weeks of age. Thoracic aortas were collected after 4 or 12 weeks of BAPN administration. False lumen formation with fresh hematomas was observed at 4 weeks of BAPN administration, indicating development of acute ADs. The false lumen developed striking remodeling at 12 weeks, suggesting progression to the chronic phase. RT-qPCR revealed that mRNA abundance of tropoelastin, a precursor of elastic fibers, was increased significantly at the chronic phase of ADs, but not at the acute phase. Tropoelastin mRNA was observed primarily in the vascular wall of the false lumen, as evidenced by in situ hybridization. Of interest, elastic fibers were formed in the wall of the false lumen in chronic ADs. These data suggest that elastic fibers were newly synthesized during the progression of ADs. Immunostaining revealed that the walls of true and false lumens of chronic ADs were mainly composed of cells expressing both αSMA (encoding by Acta2 ) and MYH11, common markers for smooth muscle cells (SMCs). However, in a lineage tracing study, the walls of the false lumen of chronic ADs were negative for the Acta2 lineage, suggesting that cells in the wall of the false lumen were derived from a non-SMC lineage but acquired SMC properties during AD progression. Bulk RNA sequencing identified the increased abundance of 2,799 genes in chronic ADs and 102 transcription factors were predicted to regulate these genes. Among them, JunB was the most abundant molecule that can be aligned in the promotor region of tropoelastin. Of note, JunB was expressed adjacent to both αSMA-positive cells and new elastic fibers in the dissected aortas. Conclusion: ADs exhibit vascular remodeling with newly elastic fiber formation by non-SMC lineage cells during the disease progression.

Abstract 17622: CCN3 Deficiency in Myeloid Cells Exacerbates Aortic Dissection by Governing a Proinflammatory Program in Macrophages

Introduction: Aortic dissection (AD) is a fatal disease. Macrophages are known central regulators of aortic inflammation and elastic fiber disruption, two major hallmarks of AD. Cellular communication network factor 3 (CCN3/NOV) is a matricellular protein associated with various biological cellular functions in cardiovascular disease and cancers. Emerging evidence strongly implicates a protective role of CCN3 against several types of vascular pathologies, however its role in AD remains unknown. Hypothesis: CCN3 deficiency in myeloid cells promotes AD development in murine models through the modulation of macrophage phenotype. Aims: We investigated the causal role of CCN3 loss in AD pathogenesis, focusing on its role in macrophages. Methods: 3-4-week-old male myeloid-specific CCN3 knockout mice (CCN3F/F;LysMCre) and control mice (LysMCre) were given BAPN (β-aminopropionitrile monofumarate; 0.2%) in their drinking water for 4 weeks for AD modeling. Mouse survival rate and histological changes of the aorta were assessed. Single cell RNA sequencing analysis was performed to recapitulate cellular transcriptome profile changes. Finally, gain and loss of function studies in bone marrow-derived macrophages (BMDMs) were performed to decipher the underlying mechanism by which CCN3 controls macrophage plasticity. Results: Following BAPN administration, myeloid-specific CCN3 knockout mice had a higher mortality rate due to AD formation and aortic rupture. In accordance with this phenotype, vascular media thickness was markedly reduced, and elastic fiber fragmentation and macrophage infiltration were elevated in myeloid-specific CCN3 knockout mice. Using single-cell RNA-seq, we found that myeloid-deficiency of CCN3 was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages. Furthermore, CCN3 deficient BMDMs are prone to M1 macrophage polarization, an effect dependent on the activation of the JAK/STAT1 signaling pathway. Conclusions: Myeloid-deficiency of CCN3 drives vascular macrophages toward an M1-like, pathogenic phenotype and promotes dissecting aortic aneurysm.

Independent and Interactive Roles of Immunity and Metabolism in Aortic Dissection.

Aortic dissection (AD) is a cardiovascular disease that seriously endangers the lives of patients. The mortality rate of this disease is high, and the incidence is increasing annually, but the pathogenesis of AD is complicated. In recent years, an increasing number of studies have shown that immune cell infiltration in the media and adventitia of the aorta is a novel hallmark of AD. These cells contribute to changes in the immune microenvironment, which can affect their own metabolism and that of parenchymal cells in the aortic wall, which are essential factors that induce degeneration and remodeling of the vascular wall and play important roles in the formation and development of AD. Accordingly, this review focuses on the independent and interactive roles of immunity and metabolism in AD to provide further insights into the pathogenesis, novel ideas for diagnosis and new strategies for treatment or early prevention of AD.

Gut Microbiota-Derived Tryptophan Metabolite Indole-3-aldehyde Ameliorates Aortic Dissection.

Tryptophan, an essential dietary amino acid, is metabolized into various metabolites within both gut microbiota and tissue cells. These metabolites have demonstrated potential associations with panvascular diseases. However, the specific relationship between tryptophan metabolism, particularly Indole-3-aldehyde (3-IAId), and the occurrence of aortic dissection (AD) remains unclear. 3-IAId showed an inverse association with advanced atherosclerosis, a risk factor for AD. In this study, we employed a well-established β-aminopropionitrile monofumarate (BAPN)-induced AD murine model to investigate the impact of 3-IAId treatment on the progression of AD. Our results reveal compelling evidence that the administration of 3-IAId significantly mitigated aortic dissection and rupture rates (BAPN + 3-IAId vs. BAPN, 45% vs. 90%) and led to a notable reduction in mortality rates (BAPN + 3-IAId vs. BAPN, 20% vs. 55%). Furthermore, our study elucidates that 3-IAId exerts its beneficial effects by inhibiting the phenotype transition of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state. It also mitigates extracellular matrix degradation, attenuates macrophage infiltration, and suppresses the expression of inflammatory cytokines, collectively contributing to the attenuation of AD development. Our findings underscore the potential of 3-IAId as a promising intervention strategy for the prevention of thoracic aortic dissection, thus providing valuable insights into the realm of vascular disease management.

Abstract P2140: Orally Delivered Modified Citrus Pectin Attenuates Aortic Dissection Development By Regulating Macrophage Pyroptosis Via Ierruption Of Galectin-3 And Toll-like Receptor 4 Interaction

Background: Aortic dissection (AD) is a lethal vascular disease caused by the formation of hematoma in the middle layer of the aortic wall. Inflammation and oxidative stress play important roles in the development of AD. Galectin-3 (Gal-3) is a 26-kDa lectin recognized to regulate many aspects of inflammatory cell behavior. Modified citrus pectin (MCP) is a pH-modified form of the dietary soluble citrus peel fiber known as pectin. It is abundant in β-galactose, which allows it to bind to Gal-3, and is recommended as a therapeutic agent for immune support, cancer, toxicity, and fibrotic diseases. The aim of this study was to explore the effect of MCP on AD and its potential mechanism involved. Methods and Results: MCP (100mg/kg) was orally administrated once every two days to retard the development of 3-aminopropionitrile fumarate/angiotensin II-induced AD animal models. In vivo, AD aorta presented an increase in Gal-3 levels that were accompanied by an increase in macrophage. Treatment with MCP decreased the incidence and mortality of AD by reducing inflammatory cell infiltration to the aorta; it downregulated the gene expression of inflammation and pyroptosis, such as IL-6, TNF-α, NLRP3, caspase-1, and IL-1β. In vitro, MCP could inhibit macrophage pyroptosis in H 2 O 2 -stimulated Raw264.7 cells. Additionally, Gal-3 is directly bound to TLR4 in H 2 O 2 -induced macrophages but MCP almost completely disrupted their interaction and suppressed activation of NF-KB by co-immunoprecipitation assays. Conclusions: Gal-3 could be a new molecular mechanism associated with AD disease, implying the use of MCP as a promising therapeutic strategy to prevent AD development.

MiR-146b Nanoparticles Alleviate Aortic Dissection via Targeting of Phosphoinositide-3-Kinase–Protein Kinase B (PI3K/Akt) Signaling Pathway

Aortic dissection (AD) has a rapid onset and a high mortality. This study explored mechanism of miR-146b and PI3k/Akt on aortic dissection. Human aortic vascular smooth muscle cells (T/GHA-VSMC) were assigned into blank group, empty vector group, miR-146b group and miR-146b group with nanoparticles as carrier (vector+miR-146b group), followed by analysis of cell proliferation, apoptosis and migration. Results showed that, expressions of PI3k/Akt, miR-146b and cell proliferation in the empty vector, miR-146b, and vector+miR-146b groups were lower than in the blank group (P &lt;0.05), with lowest expression level in the empty vector group (P &lt;0.05). Moreover, cell apoptosis was increased (P &lt;0.05) and migration ability was decreased (P &lt;0.05) after transfection, and miR-146b was found to target the PI3k/Akt. Nanoparticle-mediated miR-146b can inhibit the proliferation and migration of T/GHA-VSMC in AD patients, which is related to PI3k/Akt signaling. miR-146b may become a potential molecular target for AD, which can alleviate the occurrence and development of AD.

Analysis of Inflammation-Related Genes in Patients with Stanford Type A Aortic Dissection.

Background: Aortic dissection (AD) is a life-threatening cardiovascular disease. Pathophysiologically, it has been shown that aortic wall inflammation promotes the occurrence and development of aortic dissection. Thus, the aim of the current research was to determine the inflammation-related biomarkers in AD. Methods: In this study, we conducted differentially expressed genes (DEGs) analysis using the GSE153434 dataset containing 10 type A aortic dissection (TAAD) and 10 normal samples downloaded from the Gene Expression Omnibus (GEO) database. The intersection of DEGs and inflammation-related genes was identified as differential expressed inflammation-related genes (DEIRGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for DEIRGs. We then constructed the protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and identified hub genes using the Cytoscape plugin MCODE. Finally, least absolute shrinkage and selection operator (LASSO) logistic regression was used to construct a diagnostic model. Results: A total of 1728 DEGs were identified between the TAAD and normal samples. Thereafter, 61 DEIRGs are obtained by taking the intersection of DEGs and inflammation-related genes. The GO indicated that DEIRGs were mainly enriched in response to lipopolysaccharide, in response to molecules of bacterial origin, secretory granule membrane, external side of plasma, receptor ligand activity, and signaling receptor activator activity. KEGG analysis indicated that DEIRGs were mainly enriched in cytokine-cytokine receptor interaction, TNF signaling pathway, and proteoglycans in cancer. We identified MYC, SELL, HIF1A, EDN1, SERPINE1, CCL20, IL1R1, NOD2, TLR2, CD69, PLAUR, MMP14, and HBEGF as hub genes using the MCODE plug-in. The ROC indicated these genes had a good diagnostic performance for TAAD. Conclusion: In conclusion, our study identified 13 hub genes in the TAAD. This study will be of significance for the future development of a preventive therapy of TAAD.

Etiopathogenesis of Cardiovocal Syndrome (Ortner’s Syndrome): A Systematic Review of the Literature

Cardiovocal syndrome or Ortner’s syndrome can be caused due to a myriad of etiologies in the neck or mediastinum. The syndrome can also be a consequence of many cardiac or mediastinal pathologies or even complications of surgical treatment. The objective of this research was to systematically review to provide an overview of the etiopathogenesis of Cardiovocal syndrome or Ortner’s syndrome. Cochrane Handbook for Systematic Reviews was used for the methodology of the review and the review adhered to the “Preferred Reporting Items for Systematic Review and Meta-analysis Protocols” PRISMA protocol. The database PubMed and ClinicalKey were searched using prompts “hoarseness” OR “recurrent laryngeal nerve paralysis” AND “Ortne’s syndrome” OR “Cardiovocal syndrome” OR “aneurysm” OR “thoracic aorta” OR “unilateral vocal fold paralysis.” After data extraction synthesis was done based on the 24 most relevant and recent publications reporting and outlining this condition. Newer investigative modalities like Videolaryngostroboscopy and Transcutaneous laryngeal ultrasound (TLUSG) are useful for early recognition of this condition before the development of Aortic dissection or Rupture of Aortic Aneurysm. Cardiac physicians and Otolaryngologists must remain vigilant to the sudden onset of left vocal cord palsy as it can be an early warning sign of an ominous mediastinal pathology.

Emerging Role of Non-Coding RNAs in Aortic Dissection.

Aortic dissection (AD) is a fatal cardiovascular acute disease with high incidence and mortality, and it seriously threatens patients’ lives and health. The pathogenesis of AD mainly includes vascular inflammation, extracellular matrix degradation, and phenotypic conversion as well as apoptosis of vascular smooth muscle cells (VSMCs); however, its detailed mechanisms are still not fully elucidated. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are an emerging class of RNA molecules without protein-coding ability, and they play crucial roles in the progression of many diseases, including AD. A growing number of studies have shown that the dysregulation of ncRNAs contributes to the occurrence and development of AD by modulating the expression of specific target genes or the activity of related proteins. In addition, some ncRNAs exhibit great potential as promising biomarkers and therapeutic targets in AD treatment. In this review, we systematically summarize the recent findings on the underlying mechanism of ncRNA involved in AD regulation and highlight their clinical application as biomarkers and therapeutic targets in AD treatment. The information reviewed here will be of great benefit to the development of ncRNA-based therapeutic strategies for AD patients.

C/EBPα-Mediated Transcriptional Activation of PIK3C2A Regulates Autophagy, Matrix Metalloproteinase Expression, and Phenotypic of Vascular Smooth Muscle Cells in Aortic Dissection.

Purpose To investigate the function of C/EBPα in the development of aortic dissection (AD) and the underlying mechanism. Methods Aortic vascular smooth muscle cells (VSMCs) were isolated, cultured, and identified from AD rats. Then, C/EBPα and PIK3C2A were knockdown or overexpressed by siRNA or plasmid transfection, respectively. Rapamycin or 3-MA was utilized to stimulate and restrain autophagy of VSMCs, respectively. Western blot was used to evaluate the expression levels of C/EBPα, PIK3C2A, LC3, Beclin-1, p62, MMP-2, MMP-9, α-SMA, SM-MHC, and OPN. The pathological status of aortic ring was evaluated by stretch stress, and ChIP assay was used to analyze the binding between C/EBPα and PIK3C2A. C/EBPα shRNA was injected into tail vein to observe the effect of C/EBPα knockdown in vivo on phenotype, autophagy of aortic vascular tissue by immunohistochemical staining and Western blot. Results The protein levels of C/EBPα, PIK3C2A, MMP-2, MMP-9, and LC3 in the aorta of AD rats were all upregulated significantly. C/EBPα and rapamycin promoted notable upregulation of the synthesized proteins (OPN), PIK3C2A, matrix metalloproteinases, LC3, and Beclin-1 in VSMCs, while suppressed contractile proteins (α-SMA and SM-MHC) and p62. The opposite results were observed in the C/EBPα-knockdown VSMCs, PIK3C2A-knockdown VSMCs, or VSMCs treated with 3-MA. C/EBPα, PIK3C2A, and LC3 were dramatically upregulated by the stimulation of 3 g and 5 g stretch stress. The downregulated contractile proteins, upregulated synthetic proteins, activated autophagy, and aggravated pathological state in 5 g stretch stress-treated aortic rings were significantly reversed by the knockdown of C/EBPα. ChIP results indicated that there was a binding site for C/EBPα in the promoter of PIK3C2A. C/EBPα also downregulated α-SMA level and upregulated OPN levels in AD rats in vivo. Conclusion Our data indicated that during the development of AD, C/EBPα regulated the transition of VSMC phenotype and extracellular matrix remodeling by activating autophagy through regulating the transcriptional activity of PIK3C2A promoter.

The diagnostic significance of integrating m6A modification and immune microenvironment features based on bioinformatic investigation in aortic dissection.

PurposeThe aim of this study was to investigate the role of m6A modification and the immune microenvironment (IME) features in aortic dissection (AD) and establish a clinical diagnostic model for AD based on m6A and IME factors.MethodsGSE52093, GSE98770, GSE147026, GSE153434, and GSE107844 datasets were downloaded from the GEO database. The expression of 21 m6A genes including m6A writers, erasers, readers, and immune cell infiltrates was analyzed in AD and healthy samples by differential analysis and ssGSEA method, respectively. Both correlation analyses between m6A genes and immune cells were conducted by Pearson and Spearman analysis. XGboost was used to dissect the major m6A genes with significant influences on AD. AD samples were classified into two subgroups via consensus cluster and principal component analysis (PCA) analysis, respectively. Among each subgroup, paramount IME features were evaluated. Random forest (RF) was used to figure out key genes from AD and healthy shared differentially expressed genes (DEGs) and two AD subgroups after gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, we constructed an AD diagnostic model combining important m6A regulatory genes and assessed its efficacy.ResultsAmong 21 m6A genes, WTAP, HNRNPC, and FTO were upregulated in AD samples, while IGF2BP1 was downregulated compared with healthy samples. Immune cell infiltrating analysis revealed that YTHDF1 was positively correlated with γδT cell level, while FTO was negatively correlated with activated CD4+ T cell abundance. FTO and IGF2BP1 were identified to be crucial genes that facilitate AD development according to the XGboost algorithm. Notably, patients with AD could be classified into two subgroups among which 21 m6A gene expression profiles and IME features differ from each other via consensus cluster analysis. The RF identified SYNC and MAPK1IP1L as the crucial genes from common 657 shared common genes in 1,141 DEGs between high and low m6A scores of AD groups. Interestingly, the AD diagnostic model coordinating SYNC and MAPK1IP1L with FTO and IGF2BP1 performed well in distinguishing AD samples.ConclusionThis study indicated that FTO and IGF2BP1 were involved in the IME of AD. Integrating FTO and IGF2BP1 and MAPK1IP1L key genes in AD with a high m6A level context would provide clues for forthcoming AD diagnosis and therapy.

NORAD Promotes the Viability, Migration, and Phenotypic Switch of Human Vascular Smooth Muscle Cells during Aortic Dissection via LIN28B-Mediated TGF-β Promotion and Subsequent Enhanced Glycolysis.

Glucose metabolism reprogramming is an important reason for the functional remodeling, growth, and migration of vascular smooth muscle cells (VSMCs). It is also an important basis for the occurrence and development of aortic dissection (AD), but the specific regulatory factors are not clear. Noncoding RNA activated by DNA damage (NORAD) is dysfunctional in many diseases, but the role of NORAD in AD etiology is unclear. We first established a vascular remodeling cell model of AD, and the expression of NORAD in VSMCs was significantly increased. Functional experiments showed that inhibition of NORAD could downregulate the proliferation and migration of VSMCs. Meanwhile, silencing NORAD could also inhibit the flux of glycolysis, suggesting that NORAD may aggravate AD by promoting glycolysis. In addition, mechanism studies have shown that NORAD can exert VSMCs-regulating function by recruiting LIN28B to bind to TGF-β mRNA, which subsequently facilitates the expression of TGF-β1 (transforming growth factor β1). The recovery experiment also showed that overexpression of TGF-β could reverse the inhibitory effect of NORAD knockdown on VSMCs in terms of proliferation, migration, and glycolysis. Collectively, these results indicated that the NORAD/LIN28B/TGF-β axis promoted cell proliferation and migration through regulating aerobic glycolysis in VSMCs. Therefore, NORAD may regulate the occurrence of AD by affecting the reprogramming of glucose metabolism, and NORAD can be recognized as a good target for VSMC phenotypic intervention and AD treatment.