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Advanced Science (Weinheim,... Jul 2023Exposure to micro- and nanoplastics (MNPs) is common because of their omnipresence in environment. Recent studies have revealed that MNPs may cause atherosclerosis, but...
Exposure to micro- and nanoplastics (MNPs) is common because of their omnipresence in environment. Recent studies have revealed that MNPs may cause atherosclerosis, but the underlying mechanism remains unclear. To address this bottleneck, ApoE mice are exposed to 2.5-250 mg kg polystyrene nanoplastics (PS-NPs, 50 nm) by oral gavage with a high-fat diet for 19 weeks. It is found that PS-NPs in blood and aorta of mouse exacerbate the artery stiffness and promote atherosclerotic plaque formation. PS-NPs activate phagocytosis of M1-macrophage in the aorta, manifesting as upregulation of macrophage receptor with collagenous structure (MARCO). Moreover, PS-NPs disrupt lipid metabolism and increase long-chain acyl carnitines (LCACs). LCAC accumulation is attributed to the PS-NP-inhibited hepatic carnitine palmitoyltransferase 2. PS-NPs, as well as LCACs alone, aggravate lipid accumulation via upregulating MARCO in the oxidized low-density lipoprotein-activated foam cells. Finally, synergistic effects of PS-NPs and LCACs on increasing total cholesterol in foam cells are found. Overall, this study indicates that LCACs aggravate PS-NP-induced atherosclerosis by upregulating MARCO. This study offers new insight into the mechanisms underlying MNP-induced cardiovascular toxicity, and highlights the combined effects of MNPs with endogenous metabolites on the cardiovascular system, which warrant further study.
Topics: Animals; Mice; Microplastics; Polystyrenes; Atherosclerosis; Plaque, Atherosclerotic; Aorta
PubMed: 37144527
DOI: 10.1002/advs.202205876 -
Nature Communications Sep 2023Reprogramming of vascular smooth muscle cell (VSMC) differentiation plays an essential role in abdominal aortic aneurysm (AAA). However, the underlying mechanisms are...
Reprogramming of vascular smooth muscle cell (VSMC) differentiation plays an essential role in abdominal aortic aneurysm (AAA). However, the underlying mechanisms are still unclear. We explore the expression of FAM3A, a newly identified metabolic cytokine, and whether and how FAM3A regulates VSMC differentiation in AAA. We discover that FAM3A is decreased in the aortas and plasma in AAA patients and murine models. Overexpression or supplementation of FAM3A significantly attenuate the AAA formation, manifested by maintenance of the well-differentiated VSMC status and inhibition of VSMC transformation toward macrophage-, chondrocyte-, osteogenic-, mesenchymal-, and fibroblast-like cell subpopulations. Importantly, FAM3A induces KLF4 ubiquitination and reduces its phosphorylation and nuclear localization. Here, we report FAM3A as a VSMC fate-shaping regulator in AAA and reveal the underlying mechanism associated with KLF4 ubiquitination and stability, which may lead to the development of strategies based on FAM3A to restore VSMC homeostasis in AAA.
Topics: Animals; Humans; Mice; Aorta; Aortic Aneurysm, Abdominal; Cell Differentiation; Cytokines; Muscle, Smooth, Vascular; Ubiquitination
PubMed: 37660071
DOI: 10.1038/s41467-023-41177-x -
Cell Communication and Signaling : CCS Jul 2023Although antiangiogenic therapy has been used in gastric cancer, disease progression due to drug resistance remains common. Neutrophils play an important role in the...
Although antiangiogenic therapy has been used in gastric cancer, disease progression due to drug resistance remains common. Neutrophils play an important role in the occurrence and progression of cancer via neutrophil extracellular traps (NETs). However, few studies have investigated angiogenic regulation in gastric cancer. We aimed to determine the role of NETs in promoting angiogenesis in gastric cancer. Multiple immunohistochemical staining was used to analyze the spatial distribution of NETs and microvessels in patient tissue samples. A mouse subcutaneous tumor model was established to determine the effect of NETs on tumor growth, and changes in microvessel density were observed via immunohistochemical staining. We screened differentially expressed proteins in HUVECs stimulated by NETs via proteomics. Cell Counting Kit-8, EdU labeling, and tubule formation assays were used to verify the effect of NETs on HUVEC proliferation, migration, and tubule formation. Blocking NETs, which was related to decreased microvessel density, significantly inhibited tumor growth in the murine subcutaneous tumor model. Compared with those of the control group, tumor volume and mass among mice in the inhibition group decreased by 61.3% and 77.9%, respectively. The NET-DNA receptor CCDC25 was expressed in HUVECs, providing a platform for NETs to promote HUVEC proliferation, migration, and tubulation. In an in vitro rat aortic explant model, NETs induced HUVEC proliferation, survival, and chemotaxis, which were not significantly different from those observed in the VEGF stimulation group. Our results confirm that NETs promote angiogenesis in gastric cancer, providing a theoretical basis for identifying new anti-vascular therapeutic targets. Video Abstract.
Topics: Animals; Mice; Rats; Stomach Neoplasms; Extracellular Traps; Neutrophils; Aorta; Biological Assay; Disease Models, Animal
PubMed: 37480055
DOI: 10.1186/s12964-023-01196-z -
Experimental & Molecular Medicine Dec 2023Aortic aneurysm is a chronic disease characterized by localized expansion of the aorta, including the ascending aorta, arch, descending aorta, and abdominal aorta.... (Review)
Review
Aortic aneurysm is a chronic disease characterized by localized expansion of the aorta, including the ascending aorta, arch, descending aorta, and abdominal aorta. Although aortic aneurysms are generally asymptomatic, they can threaten human health by sudden death due to aortic rupture. Aortic aneurysms are estimated to lead to 150,000 ~ 200,000 deaths per year worldwide. Currently, there are no effective drugs to prevent the growth or rupture of aortic aneurysms; surgical repair or endovascular repair is the only option for treating this condition. The pathogenic mechanisms and therapeutic targets for aortic aneurysms have been examined over the past decade; however, there are unknown pathogenic mechanisms involved in cellular heterogeneity and plasticity, the complexity of the transforming growth factor-β signaling pathway, inflammation, cell death, intramural neovascularization, and intercellular communication. This review summarizes the latest research findings and current pathogenic mechanisms of aortic aneurysms, which may enhance our understanding of aortic aneurysms.
Topics: Humans; Aortic Aneurysm, Thoracic; Chronic Disease; Aortic Rupture; Aorta
PubMed: 38036736
DOI: 10.1038/s12276-023-01130-w -
Scandinavian Journal of Trauma,... Oct 2023Resuscitative endovascular balloon occlusion of the aorta (REBOA) is increasingly used. The recently published UK-REBOA trial aimed to investigate patients suffering...
BACKGROUND
Resuscitative endovascular balloon occlusion of the aorta (REBOA) is increasingly used. The recently published UK-REBOA trial aimed to investigate patients suffering haemorrhagic shock and randomized to standard care alone or REBOA as adjunct to standard care and concludes that REBOA may increase the mortality.
MAIN BODY
In this commentary we try to balance the discussion on use of REBOA and address limitations in the UK-REBOA trial that may have influenced the outcome of the study.
CONCLUSION
The situation is complex, and the patients are in extremis. In summary, we do not think this is the end of balloons.
Topics: Humans; Aorta; Balloon Occlusion; Endovascular Procedures; Resuscitation; Shock, Hemorrhagic; United Kingdom; Randomized Controlled Trials as Topic
PubMed: 37908007
DOI: 10.1186/s13049-023-01142-5 -
Clinical Science (London, England :... Aug 2023Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a... (Review)
Review
Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.
Topics: Humans; Aortic Aneurysm, Abdominal; Aorta, Abdominal; Doxycycline; Aortic Rupture; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 37559446
DOI: 10.1042/CS20220795 -
Hypertension (Dallas, Tex. : 1979) Oct 2023While coarctation of the aorta varies greatly in both severity and age at presentation, all patients are at increased risk of hypertension both before and after repair.... (Review)
Review
While coarctation of the aorta varies greatly in both severity and age at presentation, all patients are at increased risk of hypertension both before and after repair. Despite advances in knowledge about genetic etiologies, pathophysiologic mechanisms, and optimal repair strategies, patients with repaired coarctation of the aorta remain at increased risk of acquired cardiovascular disease. The aims of this review are to describe the management of coarctation of the aorta at all ages before and after repair, highlight pathophysiologic mechanisms of hypertension, and review long-term follow-up considerations.
Topics: Humans; Aortic Coarctation; Longevity; Ductus Arteriosus; Aorta; Hypertension
PubMed: 37476999
DOI: 10.1161/HYPERTENSIONAHA.123.19454 -
Indian Journal of Pathology &... 2024Shaggy aorta is defined as "very extensive atheromatous disease with diffuse ulcers associated with soft, loosely held debris and a paucity of actual thrombus" and often...
AIMS
Shaggy aorta is defined as "very extensive atheromatous disease with diffuse ulcers associated with soft, loosely held debris and a paucity of actual thrombus" and often results in visceral or peripheral arterial embolization (shaggy aorta syndrome). Most of the studies are clinico-radiological with hardly any assessment of the pathological features. We present an autopsy analysis of shaggy aorta.
MATERIALS AND METHODS
A retrospective study of autopsied cases of shaggy aorta over 15 years was conducted. The involvement of the various segments of the aorta (ascending, transverse, thoracic, and abdominal) was correlated with the clinical manifestations and cardiac/extra-cardiac findings at autopsy. The mortality was categorized as those related to shaggy aorta (Group I), related to cardiac diseases (Group II), and those unrelated to cardiovascular diseases (Group III).
STATISTICAL ANALYSIS
Nil.
RESULTS
In a span of 15 years, there were 76 cases of shaggy aorta affecting predominantly males (85.5%) and patients in the sixth decades of life (mean age of 64.5 years). The important associated cardiovascular risk factors included hypertension, tobacco use, and diabetes mellitus. Predominant involvement of the entire aorta and arch + descending aorta was seen in 39.5% and 35.5% of the cases, respectively. Regardless of extreme severity, only half of the patients (37 cases, 48. 7%) had clinical presentation due to shaggy aorta.
CONCLUSIONS
The occurrence of shaggy aorta may be more common than expected, and it would be important to keep this possibility in mind even in asymptomatic elderly patients with cardiovascular risk factors since aorto-arterial manipulations and anti-coagulant therapy can prove detrimental in such patients.
Topics: Male; Humans; Aged; Middle Aged; Female; Retrospective Studies; Aorta, Thoracic; Autopsy
PubMed: 38358195
DOI: 10.4103/ijpm.ijpm_573_22 -
Circulation Research Aug 2023Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune...
BACKGROUND
Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA.
METHODS
First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls.
RESULTS
Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) but not anti-PD-1 (anti-programmed death-1) nor anti-PD-L1 (anti-programmed death-ligand 1) treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4 (cluster of differentiation 4) T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4 Ki-67 regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)-mediated in vitro depletion versus controls.
CONCLUSIONS
We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway.
Topics: Humans; Aorta; Giant Cell Arteritis; Immune Checkpoint Inhibitors; Leukocytes, Mononuclear; T-Lymphocytes, Regulatory; CTLA-4 Antigen
PubMed: 37435729
DOI: 10.1161/CIRCRESAHA.122.322330 -
Frontiers in Immunology 2024
Topics: Humans; Aorta, Thoracic; Risk Factors; Cardiovascular Diseases
PubMed: 38495875
DOI: 10.3389/fimmu.2024.1384022