Gut microbiome sheds light on the development and treatment of abdominal aortic aneurysm.
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ABSTRACT:
SUBMITTER: Ling X
PROVIDER: S-EPMC9732037 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Gut microbiome sheds light on the development and treatment of abdominal aortic aneurysm.
Ling Xuebin X Jie Wei W Qin Xue X Zhang Shuya S Shi Kaijia K Li Tianfa T Guo Junli J
Frontiers in cardiovascular medicine 20221125
Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high disability and mortality. Its susceptible risk factors include old age, being male, smoking, hypertension, and aortic atherosclerosis. With the improvement of screening techniques, AAA incidence and number of deaths caused by aneurysm rupture increase annually, attracting much clinical attention. Due to the lack of non-invasive treatment, early detection and development of novel treatment of AAA is an urgent clinical c ...[more]
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Project description:Objectives: The pathophysiological mechanism of abdominal aortic aneurysm (AAA) remains unclear. We previously reported that Bifidobacterium adolescentis levels were reduced in the feces of patients with AAA by 16S ribosomal ribonucleic acid (RNA) gene sequencing. In this study, we increased the number of cases and conducted metagenomic analyses to examine bacterial genes associated with the pathophysiology of AAA. Methods: For gut microbiota data, feces from 55 patients with AAA and 52 patients with no history of AAA, lower extremity artery disease, or coronary artery disease (control group) were collected. Metagenomic analysis was performed by collecting raw stool samples from patients. For intestinal microbiota analysis, metagenomic analysis of the fecal samples was performed. Results: Oral bacteria, including Actinomyces oris (p <0.0001), Streptococcus salivarius (p <0.001), Lactobacillus salivarius (p <0.001), and Streptococcus sp. (p <0.001), were increased in the feces of patients with AAA. In addition, bacterial genes related to alpha lipoic acid (ALA) biosynthesis (M00882, M00883, and M00884, p <0.0001) were decreased in patients with AAA. Conclusions: In the feces of patients with AAA, there was an increase in oral bacteria, and the expression of bacterial genes related to ALA biosynthesis was reduced. The results suggest the possibility of developing gut microbial drug treatments for AAA.
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Project description:BackgroundStiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined.Methods and resultsUsing an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening precedes aneurysm growth. Finite-element analysis reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with the reduced segmental stiffness of the AAA-prone aorta (attributable to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species, attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, and attenuated apoptosis within the aortic wall, as well. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening.ConclusionsThe present study introduces the novel concept of segmental aortic stiffening as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring segmental aortic stiffening may aid the identification of patients at risk for AAA.
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Project description:BackgroundLong noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development.MethodsWe profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient ( ApoE-/-) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization.ResultsExperimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1α as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1α and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1α via recruiting the transcription factor specificity protein 1 to the promoter region.ConclusionsThe long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.
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Project description:MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.
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