LPS-LBP complex induced endothelial cell pyroptosis in aortic dissection is associated with gut dysbiosis.

Acute aortic dissection (AAD) is the most severe traumatic disease affecting the aorta. Pyroptosis-mediated vascular wall inflammation is a crucial trigger for AAD, and the exact mechanism requires further investigation. In this study, our proteomic analysis showed that Lipopolysaccharide (LPS)-binding protein (LBP) was significantly upregulated in the plasma and aortic tissue of patients with AAD. Further, 16S rRNA sequencing of stool samples suggested that patients with AAD exhibit gut dysbiosis, which may lead to an impaired intestinal barrier and LPS leakage. By comparing with control mice, we found that LBP, including Pyrin Domain Containing Protein3 (NLRP3), the CARD-containing adapter apoptosis-associated speck-like protein (ASC), and Cleaved caspase-1, were upregulated in the AAD aorta, whereas gut intestinal barrier-related proteins were downregulated. Moreover, treated with LBPK95A (an LBP inhibitor) attenuated the incidence of AAD, the expression levels of pyroptosis-related factors, and the extent of vascular pathological changes compared to those in AAD mice. In addition, LPS and LBP treatment of human umbilical vein endothelial cells (HUVECs) activated TLR4 signaling and intracellular reactive oxygen species (ROS) production, which stimulated NLRP3 inflammasome formation and mediated pyroptosis in endothelial cells. Our findings showed that gut dysbiosis mediates pyroptosis by the LPS-LBP complex, thus providing new insights into developing AAD.

Untargeted metabolomics identifies indole-3-propionic acid to relieve Ang II-induced endothelial dysfunction in aortic dissection.

Indole-3-propionic acid (IPA), a gut microbiota-derived metabolite of tryptophan, has been proven to fulfill an essential function in cardiovascular disease (CVD) and nerve regeneration disease. However, the role of IPA in aortic dissection (AD) has not been revealed. We aimed to investigate the role of IPA in the pathogenesis of AD and the underlying mechanisms of IPA in endothelial dysfunction. Untargeted metabolomics has been employed to screen the plasma metabolic profile of AD patients in comparison with healthy individuals. Network pharmacology provides insights into the potential molecular mechanisms underlying IPA. 3-aminopropionitrile fumarate (BAPN) and angiotensin II (Ang II) were administered to induce AD in mice, while human umbilical vein endothelial cells (HUVECs) were employed for in vitro validation of the signaling pathways predicted by network pharmacology. A total of 224 potentially differential plasma metabolites were identified in the AD patients, with 110 up-regulated metabolites and 114 down-regulated metabolites. IPA was the most significantly decreased metabolite involved in tryptophan metabolism. Bcl2, caspase3, and AKT1 were predicted as the target genes of IPA by network pharmacology and molecular docking. IPA suppressed Ang II-induced apoptosis, intracellular ROS generation, inflammation, and endothelial tight junction (TJ) loss. Animal experiments demonstrated that administration of IPA alleviated the occurrence and severity of AD in mice. Taken together, we identified a previously unexplored association between tryptophan metabolite IPA and AD, providing a novel perspective on the underlying mechanism through which IPA mitigates endothelial dysfunction to protect against AD.

Targeting metabolism in aortic aneurysm and dissection: from basic research to clinical applications.

Aortic aneurysm and dissection (AAD) are a group of insidious and lethal cardiovascular diseases that characterized by seriously threatening the life and health of people, but lack effective nonsurgical interventions. Alterations in metabolites are increasingly recognized as universal features of AAD because metabolic abnormalities have been identified not only in arterial tissue but also in blood and vascular cells from both patients and animal models with this disease. Over the past few decades, studies have further supported this notion by linking AAD to various types of metabolites such as those derived from gut microbiota or involved in TCA cycle or lipid metabolism. Many of these altered metabolites may contribute to the pathogenesis of AAD. This review aims to illustrate the close association between body metabolism and the occurrence and development of AAD, as well as summarize the significance of metabolites correlated with the pathological process of AAD. This provides valuable insight for developing new therapeutic agents for AAD. Therefore, we present a brief overview of metabolism in AAD biology, including signaling pathways involved in these processes and current clinical studies targeting AAD metabolisms. It is necessary to understand the metabolic mechanisms underlying AAD to provides significant knowledge for AAD diagnosis and new therapeutics for treatment.