Explore the vast range of titles available.

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.

Genetic factors are fundamental in the etiology of thoracic aortic aneurysm and dissection (TAAD), but the genetic cause is detected in only about 30% of cases. To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous CDKL1 variants [c.427T>C p.(Cys143Arg), c.617C>T p.(Ser206Leu), and c.404C>T p.(Thr135Met)] in 6 patients from 3 families with TAAD spectrum disorders. CDKL1 encodes a protein kinase involved in ciliary biology. Amino acid substitutions were predicted to affect CDKL1 catalytic activity or protein binding properties. CDKL1 was expressed in vascular smooth muscle cells in normal and diseased human aortic wall tissue. Cdkl1 knockdown and transient knockout in zebrafish resulted in intersomitic vessel (ISV) malformations and aortic dilation. Coinjection of human CDKL1wild-type RNA, but not CDKL1Cys143Arg and CDKL1Ser206Leu RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularly with ciliary transport molecules. Expression of CDKL1 variants in heterologous cells interfered with cilia formation and length, CDKL1 localization, and p38 MAPK and Vegf signaling. Our data suggest a role of CDKL1 variants in the pathogenesis of TAAD spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.

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 β-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-β signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis. How aging induces aortic aneurysm and dissection (AAD) remains unclear. Here, the authors show that aging induces miR-1204 to inhibit MYLK, promoting vascular smooth muscle cells to acquire senescence-associated secretory phenotype, resulting in vascular inflammation, and the aggravation of AAD formation.

Metabolic disturbances are hallmarks of vascular smooth muscle cell (VSMC) phenotypic transitions, which play a critical role in the pathogenesis of aortic dissection (AD). In this study, we identify and characterize glucose metabolism regulatory protein (GMRSP), a protein encoded by lncRNA H19. Using VSMC-specific GMRSP induction in knock-in mice, adeno-associated virus-mediated GMRSP overexpression, and exosomal GMRSP delivery, we demonstrate significant improvements in AD and mitochondrial dysfunction. Mechanistically, GMRSP inhibits heterogeneous nuclear ribonucleoprotein (hnRNP) A2B1-mediated alternative splicing of pyruvate kinase M (PKM) pre-mRNA, leading to reduced PKM2 production and glycolysis. This reprogramming preserves the contractile phenotype of VSMCs and prevents their transition to a proliferative state. Importantly, pharmacological activation of PKM2 via TEPP-46 abrogates the protective effects of GMRSP in vivo and in vitro. Clinical relevance is shown by elevated plasma PKM2 levels in AD patients, which correlate with poor prognosis. Collectively, these findings indicate GMRSP as a key regulator of VSMC metabolism and phenotypic stability, highlighting its potential as a therapeutic target for AD. Metabolic dysfunction is an important characteristic of vascular smooth muscle cells (VSMCs) phenotypic transition in aortic dissection. Here, the authors show lncRNA H19 could encode a peptide, GMRSP. GMRSP regulates the glycolysis by counteracting hnRNP A2B1-mediated pyruvate kinase M pre-mRNA alternative splicing and control the phenotypic transition of VSMCs.

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 β-aminopropionitrile fumarate (BAPN)-induced TAD. Methods A mouse model of TAD induced by BAPN and IL-1β -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. Highlights This study demonstrated for the first time that ACE2 deficiency attenuates the development of TAD induced by BAPN. The inhibitory effect of ACE2 deficiency on phenotypic transformation of VSMCs and inflammation may be through SIRT3 signaling pathway. Specific inhibition of SIRT3 can speed the exacerbation of TAD induced by BAPN and SIRT3 may be an important target for drug therapy of TAD.

Abnormal infiltration and activation of monocyte-derived macrophages (moMFs) contribute significantly to thoracic aortic dissection (TAD). The transcription factor RBPJ mediates canonical Notch signaling and modulates macrophage activation, but the role and mechanism of RBPJ in macrophages in TAD remains unclear. Here, we show that RBPJ was upregulated in macrophages infiltrating the aorta in TAD patients and BAPN-induced mouse model. Myeloid-specific Rbpj ablation protected mice from TAD, reducing death, aortic damage, macrophage infiltration, and M1-like polarization while enhancing M2-like polarization. Because moMFs dominate aorta as shown in public scRNA-seq data, and RBPJ is upregulated in moMFs compared with blood monocytes/macrophages, we assumed that mechanical force, specifically cyclic stretch, might be one of the environmental cues of macrophage activation in aorta. Indeed, bone marrow-derived macrophages (BMDMs) loaded with cyclic stretch upregulated RBPJ expression in a Piezo1-dependent way, accompanied by increased M1-like polarization, and Rbpj ablation cancelled the force-induced M1-like polarization. By RNA-sequencing, we found that cyclic stretch induced a metabolic reprogram of BMDMs characterized by upregulation of glycolysis-related genes and HIF1α, which was dependent on RBPJ. Further analyses showed that cyclic stretch upregulated PDK1, a negative regulator of pyruvate dehydrogenase (PDH), which was abrogated by RBPJ deficiency. Based on these findings, we administered dichloroacetate (DCA), a pan-PDK inhibitor, in TAD mice, and found that DCA significantly attenuated BAPN-induced TAD in mice. Therefore, our results demonstrate that RBPJ is required for pro-inflammatory moMFs activation, likely by mediating mechanotransduction-induced glycolysis via PDK1 upregulation, and PDK1 inhibitors such as DCA are potential therapeutics for TAD.

Marfan syndrome (MFS) is an inherited connective tissue disorder, with aortic root aneurysm and/or dissection being the most severe and life-threatening complication. These conditions have been linked to pathogenic variants in the FBN1 gene and dysregulated TGFβ signaling. Our objective was to evaluate the mRNA expression of FBN1, TGFBR1, TGFBR2, and TGFB2 in aortic tissue from MFS patients undergoing surgery for aortic dilation. This prospective study (2014–2023) included 20 MFS patients diagnosed according to the 2010 Ghent criteria, who underwent surgery for aneurysm or dissection based on Heart Team recommendations, along with 20 non-MFS controls. RNA was extracted, and mRNA levels were quantified using RT-qPCR. Patients with dissection showed significantly higher FBN1 mRNA levels [79 (48.1–110.1)] compared to controls [37.2 (25.1–79)] (p = 0.03). Conversely, TGFB2 expression was significantly lower in MFS patients [12.17 (6.54–24.70)] than in controls [44.29 (25.85–85.36)] (p = 0.029). A positive correlation was observed between higher FBN1 expression and a larger sinotubular junction diameter (r = 0.42, p = 0.07), while increased FBN1 expression was particularly evident in MFS patients with dissection. Additionally, TGFB2 expression showed an inverse correlation with ascending aortic diameter (r = 0.53, p = 0.01). In aortic tissue, we found decreased TGFB2 and receptor levels alongside increased FBN1 mRNA levels. These molecular alterations may reflect compensatory mechanisms in response to tissue damage caused by mechanical stress, leading to dysregulation of physiological signaling pathways and ultimately contributing to aortic dilation in MFS.

Protein lactylation, a novel post-translational modification (PTM), has emerged as a critical factor in disease processes related to glycolysis and immune responses. However, its role in aortic dissection (AD) has yet to be thoroughly investigated. This study aimed to investigate the involvement of protein lactylation in AD and identify key lactylation-related genes as potential diagnostic biomarkers. Transcriptomic data from public databases were analyzed to identify differentially expressed lactylation-related genes in AD. Functional enrichment analyses were performed, and Weighted Gene Co-expression Network Analysis (WGCNA) was utilized to identify gene modules associated with AD. Machine learning methods, including LASSO and Random Forest, were employed to identify key diagnostic genes. Experimental validation was performed using human aortic tissues and an AD model. Bioinformatics analysis identified 11 lactylation-related differentially expressed genes (LR-DEGs) in AD. WGCNA and machine learning revealed two optimal feature genes, PGK1 and HMGA1, which were validated in an independent dataset and demonstrated high diagnostic accuracy (AUC: PGK1 = 1, HMGA1 = 0.94). Immune infiltration analysis indicated significant correlations between these genes and specific immune cell types, suggesting a role in immune regulation. Experimental validation in human and murine AD tissues confirmed the upregulation of PGK1 and HMGA1. This study underscores the importance of lactylation in the pathogenesis of AD and identifies PGK1 and HMGA1 as key biomarkers related to lactylation. These findings enhance our understanding of the metabolic and immune mechanisms involved in AD, thereby presenting new molecular targets for diagnosis and therapeutic intervention.

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-β 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.

Adverse aortic remodeling increases the risk of aorta-related adverse events (AAEs) after thoracic endovascular aortic repair (TEVAR) and affects the overall prognosis of aortic dissection (AD). It is imperative to delve into the exploration of prognostic indicators to streamline the identification of individuals at elevated risk for postoperative AAEs, and therapeutic targets to optimize the efficacy of TEVAR for patients with AD. Here, we perform proteomic and single-cell transcriptomic analyses of peripheral blood and aortic lesions, respectively, from patients with AD and healthy subjects. The integrated multi-omics profiling identifies that highly phenotype-associated macrophages orchestrate neutrophil extracellular traps (NETs) through CXCL3/CXCR2 axis, thereby promoting the development of AD. Increased NETs formation is a defining feature of systemic immunity and aortic microenvironment of AD. Inhibiting NETs formation through the blockade of citrullinated histone H3 or CXCL3/CXCR2 axis ameliorates the progression and rupture of aortic dissection in male mice. The plasma level of citrullinated histone H3 predicts AAEs following endovascular therapy, facilitating the risk stratification and prognostic evaluation for patients with AD. Adverse aortic remodeling after thoracic endovascular aortic repair elevates the risk of aorta-related adverse events and worsens overall prognosis in aortic dissection (AD), highlighting the need for prognostic indicators and therapeutic targets to enhance TEVAR efficacy. Here, the authors show that inhibiting neutrophil extracellular traps ameliorates the progression of AD in mice, and that citrullinated histone H3 facilitates the risk stratification and prognostic evaluation of patients with AD.