Prognostic value of interleukin-33, sST2, myeloperoxidase, and matrix metalloproteinase-9 in acute aortic dissection. Frontiers in cardiovascular medicine Background and purpose:Acute aortic dissection (AAD) is a life-threatening cardiovascular emergency. Both neutrophil granzyme and interleukin (IL)-33/ST2 systems have proven to be effective diagnostic markers for AAD. This study aimed to investigate the relationship between plasma IL-33, soluble suppression of tumorigenesis-2 (sST2), myeloperoxidase (MPO), and matrix metalloproteinase (MMP)-9 levels at admission and all-cause mortality in patients with AAD. Methods:A total of 155 patients with AAD were enrolled from the Prospective Evaluation of Acute Chest Pain (PEACP) study. Plasma concentrations of IL-33, sST2, and MMP-9 were measured using an enzyme-linked immunosorbent assay, and MPO was detected using a chemiluminescence immunoassay. Aortic anatomical parameters were measured using CT radiography. The primary endpoint was all-cause mortality rate. Results:The median age of the patients was 55 years, and 96 (61.9%) were diagnosed with type A-AAD. After adjusting for confounding factors, the highest tertiles of IL-33, sST2, MPO, and MMP-9 had hazard risks of 0.870 (95% CI: 0.412-1.836, = 0.714), 3.769 (95% CI: 1.504-9.446, = 0.005), 4.689 (95% CI: 1.985-11.076, < 0.001), and 4.748 (95% CI: 1.763-12.784, = 0.002), respectively, compared to the lowest tertile. Pearson's correlation analysis revealed a significant correlation between these markers ( < 0.001). Moreover, sST2, MPO, and MMP-9 levels had a significant positive correlation with aortic diameter and pseudolumen area ( < 0.001). Conclusion:The biomarkers sST2, MPO, and MMP-9 were independently associated with mortality in patients with AAD. The significant correlation between these biomarkers suggests a pathogenic role for the IL-33/ST2/neutrophil granzyme system in patients with AAD. 10.3389/fcvm.2022.1084321

Upregulation of miR-222-3p alleviates the symptom of aortic dissection through targeting STAT3. Life sciences OBJECTIVE:This study sought to investigate the differentially expressed miRNAs in Aortic dissection (AD) and explore the downstream mechanisms in regulating AD. METHODS:Exosomes of AD patients and healthy people were isolated by differential centrifugation, and the differentially expressed miRNAs were evaluated by RNA sequencing. The downstream target of miR-222-3p was predicted by bioinformatics method and validated by dual-luciferase assay. Angiotensin II and Promethazine were used to establish AD mouse model and platelet-derived growth factor BB (PDGF-BB) was used to induce human vascular smooth muscle cells (HVSMCs) to elucidate the effect of miR-222-3p upregulation on AD in vivo and in vitro. The relative level of miR-222-3p was evaluated by RT-qPCR. The level of several proteins was investigated by Western blot. Immunofluorescence staining was used to detect the stress fiber formation. Cell migration was evaluated by wound healing and Transwell assay. The proliferation, cell cycle and apoptosis of HVSMCs were assessed by CCK-8 and flow cytometry, respectively. RESULTS:MiR-222-3p was downregulated in AD and PDGF-BB induced HVSMCs. The upregulation of miR-222-3p alleviated the symptom of AD in vivo by targeting STAT3, and inhibited stress fiber formation, abnormal migration, proliferation and apoptosis of HVSMCs induced by PDGF-BB by regulating the expression of α-SMA, SM22α, MMP2, MMP9 and p-Smad2. CONCLUSION:The upregulation of miR-222-3p attenuates the progression of AD. Our study provides a theoretical basis for exploring new strategies against AD. 10.1016/j.lfs.2022.121051

Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture. Circulation BACKGROUND:The development of thoracic aortic dissection (TAD) is closely related to extracellular matrix degradation and vascular smooth muscle cell (VSMC) transformation from contractile to synthetic type. LGMN (legumain) degrades extracellular matrix components directly or by activating downstream signals. The role of LGMN in VSMC differentiation and the occurrence of TAD remains elusive. METHODS:Microarray datasets concerning vascular dissection or aneurysm were downloaded from the Gene Expression Omnibus database to screen differentially expressed genes. Four-week-old male knockout mice (Lgmn), macrophage-specific knockout mice (Lgmn;LysM), and RR-11a-treated C57BL/6 mice were given BAPN (β-aminopropionitrile monofumarate; 1 g/kg/d) in drinking water for 4 weeks for TAD modeling. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Cell interaction was examined in macrophage and VSMC coculture system. The reciprocity of macrophage-derived LGMN with integrin αvβ3 in VSMCs was tested by coimmunoprecipitation assay and colocalization analyses. RESULTS:Microarray datasets from the Gene Expression Omnibus database indicated upregulated LGMN in aorta from patients with TAD and mice with angiotensin II-induced AAA. Elevated LGMN was evidenced in aorta and sera from patients with TAD and mice with BAPN-induced TAD. BAPN-induced TAD progression was significantly ameliorated in Lgmn-deficient or inhibited mice. Macrophage-specific deletion of alleviated BAPN-induced extracellular matrix degradation. Unbiased profiler polymerase chain reaction array and Gene Ontology analysis displayed that regulated VSMC phenotype transformation. Macrophage-specific deletion of ameliorated VSMC phenotypic switch in BAPN-treated mice. Macrophage-derived LGMN inhibited VSMC differentiation in vitro as assessed by macrophages and the VSMC coculture system. Macrophage-derived LGMN bound to integrin αvβ3 in VSMCs and blocked integrin αvβ3, thereby attenuating Rho GTPase activation, downregulating VSMC differentiation markers and eventually exacerbating TAD development. ROCK (Rho kinase) inhibitor Y-27632 reversed the protective role of LGMN depletion in vascular dissection. CONCLUSIONS:LGMN signaling may be a novel target for the prevention and treatment of TAD. 10.1161/CIRCULATIONAHA.121.056640

Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection. Circulation BACKGROUND:Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS:Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3 and Best3, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS:Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3 but not Best3 mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3 and ApoE mice. CONCLUSIONS:These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD. 10.1161/CIRCULATIONAHA.122.063029