Aims Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance. Methods and results We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe–/– mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD. Conclusion Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α–CREB–OGDH axis in macrophages.
Vulnerable atherosclerotic (AS) plaque is the major cause of cardiovascular death. However, clinical methods cannot directly identify the vulnerable AS plaque at molecule level. Herein, osteopontin antibody (OPN Ab) and NIR fluorescence molecules of ICG co‐assembled Ti3C2 nanosheets are reported as an advanced nanoprobe (OPN Ab/Ti3C2/ICG) with enhanced photoacoustic (PA) performance for direct and non‐invasive in vivo visual imaging of vulnerable AS plaque. The designed OPN Ab/Ti3C2/ICG nanoprobes successfully realize obvious NIR fluorescence imaging toward foam cells as well as the vulnerable AS plaque slices. After intravenous injection of OPN Ab/Ti3C2/ICG nanoprobes into AS model mice, in vivo imaging results show a significantly enhanced PA signal in the aortic arch accumulated with vulnerable plaque, well indicating the remarkable feasibility of OPN Ab/Ti3C2/ICG nanoprobes to distinguish the vulnerable AS plaque. The proposed OPN Ab/Ti3C2/ICG nanoprobes not only overcome the clinical difficulty to differentiate vulnerable plaque, but also achieve the non‐invasively specific in vivo imaging of vulnerable AS plaque at molecule level, greatly promoting the innovation of cardiovascular diagnosis technology.
Lysosomes and mitochondria play an important role in maintaining cell homeostasis. Visualizing the long‐term activities of lysosomes and mitochondria on the nanometer scale in live cells is essential for further understanding their functions but remains challenging due to the limitations of existing fluorescent probes, such as aggregation‐caused quenching (ACQ) effect, limited signal‐to‐noise ratio from fluorescence “always on” in the process of targeting organelle and poor photobleaching resistance. Herein, two efficient red‐emitting aggregation‐induced emission (AIE) luminogens are reported, which showed “off‐on” fluorescence characteristic and specific lysosomes as well as mitochondria targeting capability. Owing to their AIE characteristics, a Stokes’ shift larger than 100 nm, good biocompatibility, and excellent photostability, the AIE luminogens have been successfully utilized for high fidelity imaging of lysosomes and mitochondria. By virtue of these two probes, stimulated emission depletion (STED) images of dynamic lysosomal fusion and mitochondrial fission with a high resolution of 65.6 nm are obtained. Furthermore, the interactions between lysosomes and mitochondria in the process of mitophagy are recorded. This study also provides practical guidance for designing specific organelle targeting probes to support live cell dynamic super‐resolution imaging.
Aortic aneurysm is a chronic aortic disease affected by many factors. Although it is generally asymptomatic, it poses a significant threat to human life due to a high risk of rupture. Because of its strong concealment, it is difficult to diagnose the disease in the early stage. At present, there are no effective drugs for the treatment of aneurysms. Surgical intervention and endovascular treatment are the only therapies. Although current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm, the specific mechanisms remain unclear. Researchers are further exploring the pathogenesis of aneurysms to find new targets for diagnosis and treatment. To better understand aortic aneurysm, this review elaborates on the discovery history of aortic aneurysm, main classification and clinical manifestations, related molecular mechanisms, clinical cohort studies and animal models, with the ultimate goal of providing insights into the treatment of this devastating disease. The underlying problem with aneurysm disease is weakening of the aortic wall, leading to progressive dilation. If not treated in time, the aortic aneurysm eventually ruptures. An aortic aneurysm is a local enlargement of an artery caused by a weakening of the aortic wall. The disease is usually asymptomatic but leads to high mortality due to the risk of artery rupture.
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