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BACKGROUND: Percutaneous coronary intervention (PCI) has become the primary treatment for coronary artery disease. However, while PCI effectively addresses severe stenosis or occlusive lesions in target vessels, the progression of non-target vessel plaque remains a critical determinant of long-term patient prognosis. AIMS: The purpose of this study was to investigate the impact of non-target vascular plaque progression on prognosis after PCI for ISR. METHODS: This study included 195 patients diagnosed with ISR and multivessel disease who underwent successful PCI with drug-eluting stent (DES) placement, along with intraoperative optical coherence tomography (OCT) assessment of the culprit stent. Subsequent rechecked coronary angiography categorized eligible patients into non-target lesion progression (N-TLP) and no-N-TLP groups. We evaluated the baseline morphological characteristics of N-TLP by OCT and investigated the relationship between N-TLP, non-culprit vessel-related major adverse cardiovascular events (NCV-MACE), and pan-vascular disease-related clinical events (PVD-CE) incidence. RESULTS: Multivariate logistic regression analysis revealed that diabetes mellitus (OR 3.616, 95% CI: 1.735-7.537; Pâ¯=â¯0.001), uric acid level (OR 1.005, 95% CI: 1.001-1.009; Pâ¯=â¯0.006), in-stent neoatherosclerosis (ISNA) (OR 1.334, 95% CI: 1.114-1.985; Pâ¯=â¯0.047) and heterogeneous neointima morphology (OR 2.48, 95% CI: 1.18-5.43; Pâ¯=â¯0.019) were independent predictors for N-TLP. Furthermore, N-TLP was associated with a high incidence of NCV-MACE (19.4% vs 6.9%, Pâ¯=â¯0.009) and PVD-CE (83.9% [95% CI: 79.7%-88.3%] vs 93.1% [95% CI: 88.4%-98.0%], Pâ¯=â¯0.038) after PCI in ISR patients. CONCLUSION: Diabetes, uric acid levels, ISNA, and heterogeneous neointima are predictive factors for subsequent rapid plaque progression, with N-TLP exacerbating the incidence of NCV-MACE and PVD-CE after PCI.
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Functional tricuspid regurgitation (FTR) is the most common TR, although experimental models to effectively study it are scarce; therefore, this study aimed to establish a robust experimental swine model. A swine FTR model was developed using radiofrequency ablation, atrial septostomy, and right atrial volume overload. The baseline and follow-up echocardiography was performed to evaluate the progression FTR and changes in the heart. Autopsy was employed to verify the anatomy of tricuspid valve. One-month post intervention, among the subjects, one (8.3%) exhibited severe FTR, eight (66.7%) exhibited moderate TR, and three (25%) exhibited mild FTR. Each pig developed an atrial septal defect (diameter, 1.5 ± 0.5 cm). The tricuspid annular diameter significantly increased with enlargement of right heart (P < 0.05). No significant difference was found on left heart size and mitral regurgitation. We successfully developed a novel swine FTR model, providing a reliable and effective platform for further research on FTR.
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BACKGROUND: Hypoxia-induced pulmonary artery hypertension (HPH) is a complication of chronic hypoxic lung disease and the third most common type of pulmonary artery hypertension (PAH). Epigenetic mechanisms play essential roles in the pathogenesis of HPH. N6-methyladenosine (m6A) is an important modified RNA nucleotide involved in a variety of biological processes and an important regulator of epigenetic processes. To date, the precise role of m6A and regulatory molecules in HPH remains unclear. METHODS: HPH model and pulmonary artery smooth muscle cells (PASMCs) were constructed from which m6A changes were observed and screened for AlkB homolog 5 (Alkbh5). Alkbh5 knock-in (KI) and knock-out (KO) mice were constructed to observe the effects on m6A and evaluate right ventricular systolic pressure (RVSP), left ventricular and septal weight [RV/(LV + S)], and pulmonary vascular remodeling in the context of HPH. Additionally, the effects of Alkbh5 knockdown using adenovirus were examined in vitro on m6A, specifically in PASMCs with regard to proliferation, migration and cytochrome P450 1A1 (Cyp1a1) mRNA stability. RESULTS: In both HPH mice lung tissues and hypoxic PASMCs, a decrease in m6A was observed, accompanied by a significant up-regulation of Alkbh5 expression. Loss of Alkbh5 attenuated the proliferation and migration of hypoxic PASMCs in vitro, with an associated increase in m6A modification. Furthermore, Alkbh5 KO mice exhibited reduced RVSP, RV/(LV + S), and attenuated vascular remodeling in HPH mice. Mechanistically, loss of Alkbh5 inhibited Cyp1a1 mRNA decay and increased its expression through an m6A-dependent post-transcriptional mechanism, which hindered the proliferation and migration of hypoxic PASMCs. CONCLUSION: The current study highlights the loss of Alkbh5 impedes the proliferation and migration of PASMCs by inhibiting post-transcriptional Cyp1a1 mRNA decay in an m6A-dependent manner.
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Homólogo AlkB 5 da RNA Desmetilase , Citocromo P-450 CYP1A1 , Hipóxia , Camundongos Knockout , Artéria Pulmonar , Estabilidade de RNA , Animais , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Hipóxia/genética , Hipóxia/metabolismo , Camundongos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/metabolismo , Miócitos de Músculo Liso/metabolismo , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/etiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Masculino , Proliferação de Células , Modelos Animais de Doenças , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Remodelação Vascular/genética , Camundongos Endogâmicos C57BLRESUMO
NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation, catalyzed by the enzyme cascade, namely NEDD8 activating enzyme (E1), NEDD8 conjugating enzyme (E2), and NEDD8 ligase (E3). The substrates of neddylation are categorized into cullins and non-cullin proteins. Neddylation of cullins activates CRLs (cullin RING ligases), the largest family of E3 ligases, whereas neddylation of non-cullin substrates alters their stability and activity, as well as subcellular localization. Significantly, the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases, such as metabolic disorders, liver dysfunction, neurodegenerative disorders, and cancers, among others. Thus, targeting neddylation becomes an attractive strategy for the treatment of these diseases. In this review, we first provide a general introduction on the neddylation cascade, its biochemical process and regulation, and the crystal structures of neddylation enzymes in complex with cullin substrates; then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin substrates. We further review the literature data on dysregulated neddylation in several human diseases, particularly cancer, followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic approach. Finally, few perspectives were proposed for extensive future investigations.
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Proteínas Culina , Neoplasias , Humanos , Proteínas Culina/metabolismo , Ubiquitinas/genética , Ubiquitina-Proteína Ligases/metabolismo , Processamento de Proteína Pós-Traducional , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
Background: The relationship between neointimal characteristics of in-stent restenosis (ISR) and periprocedural myocardial injury (PMI) remains unclear. Therefore, this study aimed to investigate the relationship between PMI and neointimal characteristics of ISR by using optical coherence tomography (OCT). Methods: This was a retrospective study. We enrolled 140 patients diagnosed with ISR with normal baseline high-sensitivity troponin T (hs-cTnT) levels who underwent OCT and subsequent revascularization by means of drug-coated balloon (DCB) or drug-eluting stent (DES) between October 2018 and October 2022 in the Affiliated Hospital of Zunyi Medical University. Based on the 4th universal definition of myocardial infarction, patients whose hs-cTnT were increased five times above the upper reference limit (URL) after percutaneous coronary interventions (PCI) were deemed to PMI. The patients were subdivided into PMI (n=53) and non-PMI (n=87) groups. In the univariable analysis, variables in the baselines, angiography characteristics and OCT findings were analyzed with binary logistic regression. A P value of <0.2 was included in the multivariable model. Multivariable logistic regression analysis was used to identify the independent predictors of PMI. Results: The prevalence of intra-intimal microvessels in patients with PMI was higher than in those without PMI (58.5% vs. 32.2%, P=0.003). The ratio of intra-stent plaque rupture (PR) was also higher in patients with PMI (60.4% vs. 40.2%, P=0.021). Multivariable logistic regression analysis showed that intra-intimal microvessels [odds ratio (OR): 3.193, 95% confidence interval (CI): 1.280-7.966; P=0.013] and intra-stent PR (OR: 2.124, 95% CI: 1.153-4.732; P=0.035) were independently associated with PMI. Conclusions: Intra-intimal microvessels and intra-stent PR were independently associated with PMI. Accurate identification and recognition of intra-intimal microvessels and intra-stent PR may be helpful in preventing PMI.
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BACKGROUND: Hypothermia therapy has been suggested to attenuate myocardial necrosis; however, the clinical implementation as a valid therapeutic strategy has failed, and new approaches are needed to translate into clinical applications. This study aimed to assess the feasibility, safety, and efficacy of a novel selective intracoronary hypothermia (SICH) device in mitigating myocardial reperfusion injury. METHODS: This study comprised two phases. The first phase of the SICH was performed in a normal porcine model for 30 minutes ( n = 5) to evaluate its feasibility. The second phase was conducted in a porcine myocardial infarction (MI) model of myocardial ischemia/reperfusion was performed by balloon occlusion of the left anterior descending coronary artery for 60 minutes and maintained for 42 days. Pigs in the hypothermia group ( n = 8) received hypothermia intervention onset reperfusion for 30 minutes and controls ( n = 8) received no intervention. All animals were followed for 42 days. Cardiac magnetic resonance analysis (5 and 42 days post-MI) and a series of biomarkers/histological studies were performed. RESULTS: The average time to lower temperatures to a steady state was 4.8 ± 0.8 s. SICH had no impact on blood pressure or heart rate and was safely performed without complications by using a 3.9 F catheter. Interleukin-6 (IL-6), tumor necrosis factor-α, C-reactive protein (CRP), and brain natriuretic peptide (BNP) were lower at 60 min post perfusion in pigs that underwent SICH as compared with the control group. On day 5 post MI/R, edema, intramyocardial hemorrhage, and microvascular obstruction were reduced in the hypothermia group. On day 42 post MI/R, the infarct size, IL-6, CRP, BNP, and matrix metalloproteinase-9 were reduced, and the ejection fraction was improved in pigs that underwent SICH. CONCLUSIONS: The SICH device safely and effectively reduced the infarct size and improved heart function in a pig model of MI/R. These beneficial effects indicate the clinical potential of SICH for treatment of myocardial reperfusion injury.
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The morphological characteristics of in-stent restenosis (ISR) in relation to varying degrees of area stenosis have not been comprehensively examined. This study aimed to explore the tissue characteristics of patients experiencing ISR with different degrees of area stenosis through the utilization of optical coherence tomography (OCT). In total, 230 patients with ISR who underwent OCT were divided into the following three groups: area stenosis (AS) < 70% (n = 26); 70-80% (n = 119) and AS ≥ 80% (n = 85). Among the 230 patients, the clinical presentation as stable angina was 61.5% in AS < 70%, followed by 47.2% in 70% < AS ≤ 80%, and 31.8% in AS ≥ 80% (P = 0.010). The OCT findings showed that heterogeneous neointima, ISNA, LRP, neointima rupture, TCFA-like pattern, macrophage infiltration, red and white thrombus was more common with AS increased. Ordinal logistic regression analysis showed that higher AS was associated with previous dyslipidemia (odds ratio [OR], 4.754; 95% confidence interval [CI], 1.419-15.927, P = 0.011), neointimal rupture (OR: 3.640; 95% CI, 1.169-11.325, P = 0.026), red thrombus (OR: 4.482; 95% CI, 1.269-15.816, P = 0.020) and white thrombus (OR: 5.259; 95% CI, 1.660-16.659, P = 0.005). Patients with higher degrees of area stenosis in the context of ISR exhibited a greater number of discernible morphological characteristics as identified through OCT analysis. Furthermore, previous dyslipidemia, neointimal rupture, white thrombus and red thrombus were highly associated with and the progression of ISR lesions.
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Reestenose Coronária , Vasos Coronários , Neointima , Intervenção Coronária Percutânea , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Stents , Tomografia de Coerência Óptica , Humanos , Masculino , Feminino , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/etiologia , Reestenose Coronária/patologia , Pessoa de Meia-Idade , Idoso , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Risco , Resultado do Tratamento , Estudos Retrospectivos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Doença da Artéria Coronariana/patologia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/patologia , Estenose Coronária/terapia , Ruptura EspontâneaRESUMO
Cardiac fibroblasts (CFs) are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure (HF). TEAD1 has been shown to be essential for heart development and homeostasis. However, fibroblast endogenous TEAD1 in cardiac remodeling remains incompletely understood. Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload. Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs- and myofibroblasts-specific Cre mice. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor, VT103, ameliorated TAC-induced cardiac remodeling. Mechanistically, RNA-seq and ChIP-seq analysis identified Wnt4 as a novel TEAD1 target. TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway, and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression. Furthermore, co-immunoprecipitation combined with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4, leading to the binding and activation of the Wnt4 promoter. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.
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Fatores de Transcrição de Domínio TEA , Fatores de Transcrição , Remodelação Ventricular , Animais , Camundongos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição de Domínio TEA/genética , Fatores de Transcrição de Domínio TEA/metabolismo , Fatores de Transcrição/genética , Remodelação Ventricular/genética , Proteína Wnt4/metabolismo , Fibroblastos/metabolismo , Proteínas que Contêm Bromodomínio/metabolismoRESUMO
Background: Neoatherosclerosis (NA) is associated with stent failure. However, systematic studies on the manifestations of NA and neovascularization (NV) at different stages after drug-eluting stent (DES) implantation are lacking. Moreover, the relationship between NA and NV in in-stent restenosis (ISR) has not been reported. This study aimed to characterize NA and NV in patients with ISR at different post-DES stages and compare the association between NA and NV in ISR lesions. Methods: A total of 227 patients with 227 lesions who underwent follow-up optical coherence tomography before percutaneous coronary intervention for DES ISR were enrolled and divided into early (E-ISR: < 1 year), late (L-ISR: 1-5 years), and very-late (VL-ISR: > 5 years) ISR groups. Furthermore, ISR lesions were divided into NV and non-NV groups according to the presence of NV. Results: The prevalence of NA and NV was 52.9% and 41.0%, respectively. The prevalence of lipidic NA (E-ISR, 32.7%; L-ISR, 50.0%; VL-ISR, 58.5%) and intimal NV (E-ISR, 14.5%; L-ISR, 30.8%; VL-ISR, 38.3%) increased with time after stenting. NA was higher in ISR patients with NV lesions than in those without (p < 0.001). Patients with both ISR and NV had a higher incidence of macrophage infiltration, thin-cap fibroatheroma, intimal rupture, and thrombosis (p < 0.01). Conclusions: Progression of lipidic NA was associated with L-ISR and VL-ISR but may not be related to calcified NA. NA was more common in ISR lesions with NV; its formation may substantially promote NA progression and plaque instability.