ACE2 deficiency inhibits thoracic aortic dissection by enhancing SIRT3 mediated inhibition of inflammation and VSCMs phenotypic switch.

BACKGROUND: Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in ß-aminopropionitrile fumarate (BAPN)-induced TAD. METHODS: A mouse model of TAD induced by BAPN and IL-1ß -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. RESULTS: We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. CONCLUSION: ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.

Early growth response 1 exacerbates thoracic aortic aneurysm and dissection of mice by inducing the phenotypic switching of vascular smooth muscle cell through the activation of Krüppel-like factor 5.

AIM: Vascular smooth muscle cell (VSMC) phenotypic switching has been reported to regulate vascular function and thoracic aortic aneurysm and dissection (TAAD) progression. Early growth response 1 (Egr1) is associated with the differentiation of VSMCs. However, the mechanisms through which Egr1 participates in the regulation of VSMCs and progression of TAAD remain unknown. This study aimed to investigate the role of Egr1 in the phenotypic switching of VSMCs and the development of TAAD. METHODS: Wild-type C57BL/6 and SMC-specific Egr1-knockout mice were used as experimental subjects and fed ß-aminopropionitrile for 4 weeks to construct the TAAD model. Ultrasound and aortic staining were performed to examine the pathological features in thoracic aortic tissues. Transwell, wound healing, CCK8, and immunofluorescence assays detected the migration and proliferation of synthetic VSMCs. Egr1 was directly bound to the promoter of Krüppel-like factor 5 (KLF5) and promoted the expression of KLF5, which was validated by JASPAR database and dual-luciferase reporter assay. RESULTS: Egr1 expression increased and was partially co-located with VSMCs in aortic tissues of mice with TAAD. SMC-specific Egr1 deficiency alleviated TAAD and inhibited the phenotypic switching of VSMC. Egr1 knockdown prevented the phenotypic switching of VSMCs and subsequently suppressed the migration and proliferation of synthetic VSMCs. The inhibitory effects of Egr1 deficiency on VSMCs were blunted once KLF5 was overexpressed. CONCLUSION: Egr1 aggravated the development of TAAD by promoting the phenotypic switching of VSMCs via enhancing the transcriptional activation of KLF5. These results suggest that inhibition of SMC-specific Egr1 expression is a promising therapy for TAAD.

PANoptosis is a prominent cell death feature in thoracic aortic aneurysm or dissection.

Thoracic aortic aneurysm and dissection (TAAD) is a devastating macrovascular disease, and its pathogenic mechanisms have not been well clarified. This study aimed to investigate the role of PANoptosis, which is newly defined programmed cell death (PCD) and characterized by pyroptosis, apoptosis, and necroptosis, in the pathogenesis of TAAD. We found that the expression of initiator factor Z-DNA binding protein 1 (ZBP1) and PANoptosis-related genes were upregulated in the ß-aminopropionitrile (BAPN) + Angiotensin II (Ang II)-induced TAAD mice. Ang II stimuli enhanced the expression of ZBP1, promoted the generation of bioactive GSDMD (Gasdermin D) fragments, the cleavage of Caspase 3, and increased the phosphorylation of mixed lineage kinase domain-like pseudokinase (MLKL) in human aortic vascular smooth muscle cells (HASMCs), indicating the activation of hallmarks for PANoptosis. Moreover, ZBP1-mediated PANoptosis occurs in the aortic tissues of TAAD patients. These results highlight the significant role of PANoptosis in TAAD pathogenesis, suggesting ZBP1 and other PANoptosis-related genes as potential therapeutic targets for this condition.

CD36-mediated ferroptosis destabilizes CD4+ T cell homeostasis in acute Stanford type-A aortic dissection.

Acute type A aortic dissection (ATAAD) is a lethal pathological process within the aorta with high mortality and morbidity. T lymphocytes are perturbed and implicated in the clinical outcome of ATAAD, but the exact characteristics of T cell phenotype and its underlying mechanisms in ATAAD remain poorly understood. Here we report that CD4+ T cells from ATAAD patients presented with a hypofunctional phenotype that was correlated with poor outcomes. Whole transcriptome profiles showed that ferroptosis and lipid binding pathways were enriched in CD4+ T cells. Inhibiting ferroptosis or reducing intrinsic reactive oxygen species limited CD4+ T cell dysfunction. Mechanistically, CD36 was elevated in CD4+ T cells, whose blockade effectively alleviated palmitic acid-induced ferroptosis and CD4+ T cell hypofunction. Therefore, targeting the CD36-ferroptosis pathway to restore the functions of CD4+ T cells is a promising therapeutic strategy to improve clinical outcomes in ATAAD patients.

Developing and Verifying an Effective Diagnostic Model Linked to Immune Infiltration in Stanford Type A Aortic Dissection.

BACKGROUND: The deadly cardiovascular condition known as Stanford type A aortic dissection (TAAD) carries a high risk of morbidity and mortality. One important step in the pathophysiology of the condition is the influx of immune cells into the aorta media, which causes medial degeneration. The purpose of this work was to investigate the potential pathogenic significance of immune cell infiltration in TAAD and to test for associated biomarkers. METHODS: The National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database provided the RNA sequencing microarray data (GSE153434, GPL20795, GSE52093). Immune cell infiltration abundance was predicted using ImmuCellAI. GEO2R was used to select differentially expressed genes (DEGs), which were then processed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Additionally, hub genes linked to immune infiltration were found using functional and pathway enrichment, least absolute shrinkage and selection operator (LASSO), weighted gene co-expression network analysis (WGCNA), and differential expression analysis. Lastly, hub genes were validated and assessed using receiver operating characteristic (ROC) curves in the microarray dataset GSE52093. The hub gene expression and its connection to immune infiltration in TAAD were confirmed using both animal models and clinic data. RESULTS: We identified the most important connections between macrophages, T helper cell 17 (Th17), iTreg cells, B cells, natural killer cells and TAAD. And screened seven hub genes associated with immune cell infiltration: ABCG2, FAM20C, ELL2, MTHFD2, ANKRD6, GLRX, and CDCP1. The diagnostic model in TAAD diagnosis with the area under ROC (AUC) was 0.996, and the sensitivity was 99.21%, the specificity was 98.67%, which demonstrated a surprisingly strong diagnostic power of TAAD in the validation datasets. The expression pattern of four hub DEGs (ABCG2, FAM20C, MTHFD2, CDCP1) in clinic samples and animal models matched bioinformatics analysis, and ABCG2, FAM20C, MTHFD2 up-regulation, and the of CDCP1 down-regulation were also linked to poor cardiovascular function. CONCLUSIONS: This study developed and verified an effective diagnostic model linked to immune infiltration in TAAD, providing new approaches to studying the potential pathogenesis of TAAD and discovering new medication intervention targets.

LncRNA HCG18 affects aortic dissection through the miR-103a-3p/HMGA2 axis by modulating proliferation and apoptosis of vascular smoothing muscle cells.

BACKGROUND: Aortic Dissection (AD) is a vascular disease with a high mortality rate and limited treatment strategies. The current research analyzed the function and regulatory mechanism of lncRNA HCG18 in AD. METHODS: HCG18, miR-103a-3p, and HMGA2 levels in the aortic tissue of AD patients were examined by RT-qPCR. After transfection with relevant plasmids, the proliferation of rat aortic Vascular Smoothing Muscle Cells (VSMCs) was detected by CCK-8 and colony formation assay, Bcl-2 and Bax was measured by Western blot, and apoptosis was checked by flow cytometry. Then, the targeting relationship between miR-103a-3p and HCG18 or HMGA2 was verified by bioinformation website analysis and dual luciferase reporter assay. Finally, the effect of HCG18 was verified in an AD rat model induced by ß-aminopropionitrile. RESULTS: HCG18 and HMGA2 were upregulated and miR-103a-3p was downregulated in the aortic tissues of AD patients. Downregulating HCG18 or upregulating miR-103a-3p enhanced the proliferation of VSMCs and limited cell apoptosis. HCG18 promoted HMGA2 expression by competing with miR-103a-3p and restoring HMGA2 could impair the effect of HCG18 downregulation or miR-103a-3p upregulation in mediating the proliferation and apoptosis of VSMCs. In addition, down-regulation of HCG18 could improve the pathological injury of the aorta in AD rats. CONCLUSION: HCG18 reduces proliferation and induces apoptosis of VSMCs through the miR-103a-3p/HMGA2 axis, thus aggravating AD.

RBM15 activates glycolysis in M1-type macrophages to promote the progression of aortic aneurysm and dissection.

Aortic aneurysm and dissection (AD) represent a critical cardiovascular emergency with an alarmingly high mortality rate. Recent research has spotlighted the overexpression of genes associated with the m6A modification in AD patients, linking them to the presence of inflammatory M1-type macrophages. Moreover, glycolysis is widely recognized as a key feature of inflammatory M1-type macrophages, but biomarkers linking glycolysis and macrophage function to promote disease progression in AD have not been reported. We conducted an analysis of aortic immune cell infiltration, macrophages, and m6A-related biomarkers in AD patients using bioinformatics techniques. Subsequently, we employed a combination of RT-PCR, WB, and immunofluorescence assays to elucidate the alterations in the expression of M1- and M2-type macrophages, as well as markers of glycolysis, following the overexpression of key biomarkers. These findings were further validated in vivo through the creation of a rat model of AD with knockdown of the aforementioned key biomarkers. The findings revealed that the m6A-modified related gene RBM15 exhibited heightened expression in AD samples and was correlated with macrophage polarization. Upon overexpression of RBM15 in macrophages, there was an observed increase in the expression of M1-type macrophage markers CXCL9 and CXCL10, alongside a decrease in the expression of M2-type macrophage markers CCL13 and MRC1. Furthermore, there was an elevation in the expression of glycolytic enzymes GLUT1 and Hexokinase, as well as HIF1α, GAPDH, and PFKFB3 after RBM15 overexpression. Moreover, in vivo knockdown of RBM15 led to an amelioration of aortic aneurysm in the rat AD model. This knockdown also resulted in a reduction of the M1-type macrophage marker iNOS, while significantly increasing the expression of the M2-type macrophage marker CD206. In conclusion, our findings demonstrate that RBM15 upregulates glycolysis in macrophages, thus contributing to the progression of AD through the promotion of M1-type macrophage polarization. Conversely, downregulation of RBM15 suppresses M1-type macrophage polarization, thereby decelerating the advancement of AD. These results unveil potential novel targets for the treatment of 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.

Coding and Non-Coding Transcriptomic Landscape of Aortic Complications in Marfan Syndrome.

Marfan syndrome (MFS) is a rare congenital disorder of the connective tissue, leading to thoracic aortic aneurysms (TAA) and dissection, among other complications. Currently, the most efficient strategy to prevent life-threatening dissection is preventive surgery. Periodic imaging applying complex techniques is required to monitor TAA progression and to guide the timing of surgical intervention. Thus, there is an acute demand for non-invasive biomarkers for diagnosis and prognosis, as well as for innovative therapeutic targets of MFS. Unraveling the intricate pathomolecular mechanisms underlying the syndrome is vital to address these needs. High-throughput platforms are particularly well-suited for this purpose, as they enable the integration of different datasets, such as transcriptomic and epigenetic profiles. In this narrative review, we summarize relevant studies investigating changes in both the coding and non-coding transcriptome and epigenome in MFS-induced TAA. The collective findings highlight the implicated pathways, such as TGF-ß signaling, extracellular matrix structure, inflammation, and mitochondrial dysfunction. Potential candidates as biomarkers, such as miR-200c, as well as therapeutic targets emerged, like Tfam, associated with mitochondrial respiration, or miR-632, stimulating endothelial-to-mesenchymal transition. While these discoveries are promising, rigorous and extensive validation in large patient cohorts is indispensable to confirm their clinical relevance and therapeutic potential.

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 in vitro 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 IL1ß, IL6, TNF-α, and NLRP3, as well as the expression of apoptosis-related proteins BAX/BCL2 and Cleaved caspase3/Caspase3. In the in vivo 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.

GWAS-based polygenic risk scoring for predicting cerebral artery dissection in the Chinese population.

OBJECTIVE: Cerebral artery dissection (CeAD) is a rare but serious disease. Genetic risk assessment for CeAD is lacking in Chinese population. We performed genome-wide association study (GWAS) and computed polygenic risk score (PRS) to explore genetic susceptibility factors and prediction model of CeAD based on patients in Huashan Hospital. METHODS: A total of 210 CeAD patients and 280 controls were enrolled from June 2017 to September 2022 in Department of Neurology, Huashan Hospital, Fudan University. We performed GWAS to identify genetic variants associated with CeAD in 140 CeAD patients and 210 control individuals according to a case and control 1:1.5 design rule in the training dataset, while the other 70 patients with CeAD and 70 controls were used as validation. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were utilized to identify the significant pathways. We constructed a PRS by capturing all independent GWAS SNPs in the analysis and explored the predictivity of PRS, age, and sex for CeAD. RESULTS: Through GWAS analysis of the 140 cases and 210 controls in the training dataset, we identified 13 leading SNPs associated with CeAD at a genome-wide significance level of P < 5 × 10- 8. Among them, 10 SNPs were annotated in or near (in the upstream and downstream regions of ± 500Kb) 10 functional genes. rs34508376 (OR2L13) played a suggestive role in CeAD pathophysiology which was in line with previous observations in aortic aneurysms. The other nine genes were first-time associations in CeAD cases. GO enrichment analyses showed that these 10 genes have known roles in 20 important GO terms clustered into two groups: (1) cellular biological processes (BP); (2) molecular function (MF). We used genome-wide association data to compute PRS including 32 independent SNPs and constructed predictive model for CeAD by using age, sex and PRS as predictors both in training and validation test. The area under curve (AUC) of PRS predictive model for CeAD reached 99% and 95% in the training test and validation test respectively, which were significantly larger than the age and sex models of 83% and 86%. CONCLUSIONS: Our study showed that ten risk loci were associated with CeAD susceptibility, and annotated functional genes had roles in 20 important GO terms clustered into biological process and molecular function. The PRS derived from risk variants was associated with CeAD incidence after adjusting for age and sex both in training test and validation.

Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome.

BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by DNMT3A heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described. METHODS: Here we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition. RESULTS: We include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery. CONCLUSIONS: Arterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.

Aging aggravates aortic aneurysm and dissection via miR-1204-MYLK signaling axis in mice.

The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates ß-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-ß signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.

Iron deficiency affects oxygen transport and activates HIF1 signaling pathway to regulate phenotypic transformation of VSMC in aortic dissection.

BACKGROUND: Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration.This experiment aims to explore how iron deficiency (ID) affects the function of vascular smooth muscle cell (VSMC) and participates in the occurrence and development of AD by regulating gene expression. METHODS: The relationship between iron and AD was proved by Western-blot (WB) and immunostaining experiments in human and animals. Transcriptomic sequencing explored the transcription factors that were altered downstream. WB, flow cytometry and immunofluorescence were used to demonstrate whether ID affected HIF1 expression through oxygen transport. HIF1 signaling pathway and phenotypic transformation indexes were detected in cell experiments. The use of the specific HIF1 inhibitor PX478 further demonstrated that ID worked by regulating HIF1. RESULTS: The survival period of ID mice was significantly shortened and the pathological staining results were the worst. Transcriptomic sequencing indicated that HIF1 was closely related to ID and the experimental results indicated that ID might regulate HIF1 expression by affecting oxygen balance. HIF1 activation regulates the phenotypic transformation of VSMC and participates in the occurrence and development of AD in vivo and in vitro.PX478, the inhibition of HIF1, can improve ID-induced AD exacerbation.

[Differential expressions of endoplasmic reticulum stress-associated genes in aortic dissection and their correlation with immune cell infiltration].

OBJECTIVE: To explore differentially expressed endoplasmic reticulum stress-associated genes (ERSAGs) in aortic dissection (AD) and their correlations with immune cell infiltration to identify new therapeutic targets for AD. METHODS: Two AD mRNA expression datasets (GSE190635 and GSE98770) were downloaded from GEO database for analysis of differentially expressed genes between the aorta of AD patients and normal aorta using R software. ERSAGs dataset was downloaded from GeneCards website, and GeneMANIA database was used to analyze the protein-protein interaction network of the differentially expressed ERSAGs and the proteins interacting with these genes. Based on GSE98770 dataset we analyzed the distributions of 22 immune cells within the aortic wall of AD patients using CIBERSORT package of R software. Surgical aortic wall specimens were obtained from 10 AD patients and 10 non-AD patients for detecting AGER mRNA expression using qRTPCR, and the upstream transcriptional factors, miRNAs, and chemicals targeting AGER were analyzed using the TRRUST database and NetworkAnalyst database. RESULTS: Bioinformatic analysis suggested significant differential expression of AGER in AD, which interacted with 20 proteins involved in pattern recognition receptor signaling pathway, positive regulation of DNA-binding transcription factor activity, myeloid leukocyte migration, leukocyte migration, and regulation of the I-κB kinase/NF-κB signaling. In AD, AGER expression level was positively correlated with Treg cell abundance (r=0.59, P < 0.05). The results of qRT-PCR demonstrated significantly lower expression of AGER mRNA in AD than in non-AD patients (1.00±0.30 vs 1.76±0.68, P < 0.05). ROC curve analysis showed that at the cut-off value of 1.335, AGER had an AUC of 0.86 (95% CI: 0.67-1.00, P= 0.0073) for predicting AD. Three transcriptional factors, 3 miRNAs, and 27 chemicals were predicted in the AGER regulatory network. CONCLUSION: AGER is lowly expressed in the aorta of AD patients and may influence the occurrence of AD through Treg cells.

RNF213 Polymorphisms in Intracranial Artery Dissection.

The ring finger protein 213 gene (RNF213) is involved in several vascular diseases, both intracranial and systemic ones. Some variants are common in the Asian population and are reported as a risk factor for moyamoya disease, intracranial stenosis and intracranial aneurysms. Among intracranial vascular diseases, both moyamoya disease and intracranial artery dissection are more prevalent in the Asian population. We performed a systematic review of the literature, aiming to assess the rate of RNF213 variants in patients with spontaneous intracranial dissections. Four papers were identified, providing data on 53 patients with intracranial artery dissection. The rate of RNF213 variants is 10/53 (18.9%) and it increases to 10/29 (34.5%), excluding patients with vertebral artery dissection. All patients had the RNF213 p.Arg4810Lys variant. RNF213 variants seems to be involved in intracranial dissections in Asian cohorts. The small number of patients, the inclusion of only patients of Asian descent and the small but non-negligible coexistence with moyamoya disease familiarity might be limiting factors, requiring further studies to confirm these preliminary findings and the embryological interpretation.

MiR-1909-5p targeting GPX4 affects the progression of aortic dissection by modulating nicotine-induced ferroptosis.

OBJECTIVE: Aortic dissection (AD) is a prevalent and acute clinical catastrophe characterized by abrupt manifestation, swift progression, and elevated fatality rates. Despite smoking being a significant risk factor for AD, the precise pathological process remains elusive. This investigation endeavors to explore the mechanisms by which smoking accelerates AD through ferroptosis induction. METHODOLOGY: In this novel study, we detected considerable endothelial cell death by ferroptosis within the aortic inner lining of both human AD patients with a smoking history and murine AD models induced by ß-aminopropionitrile, angiotensin II, and nicotine. Utilizing bioinformatic approaches, we identified microRNAs regulating the expression of the ferroptosis inhibitor Glutathione peroxidase 4 (GPX4). Nicotine's impact on ferroptosis was further assessed in human umbilical vein endothelial cells (HUVECs) through modulation of miR-1909-5p. Additionally, the therapeutic potential of miR-1909-5p antagomir was evaluated in vivo in nicotine-exposed AD mice. FINDINGS: Our results indicate a predominance of ferroptosis over apoptosis, pyroptosis, and necroptosis in the aortas of AD patients who smoke. Nicotine exposure instigated ferroptosis in HUVECs, where the miR-1909-5p/GPX4 axis was implicated. Modulation of miR-1909-5p in these cells revealed its regulatory role over GPX4 levels and subsequent endothelial ferroptosis. In vivo, miR-1909-5p suppression reduced ferroptosis and mitigated AD progression in the murine model. CONCLUSIONS: Our data underscore the involvement of the miR-1909-5p/GPX4 axis in the pathogenesis of nicotine-induced endothelial ferroptosis in AD.

Early matrix softening contributes to vascular smooth muscle cell phenotype switching and aortic dissection through down-regulation of microRNA-143/145.

Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection.

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections.

Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM-VSMC network.