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Full length transcriptome sequencing of rat abdominal aorta primary EC

ABSTRACT: MicroRNAs are well established as key regulators of cellular function and viability. A growing body of evidence indicates that multiple miRNAs are involved in the formation and rupture of IAs. MicroRNA-337-3p (miR-337-3p), in particular, has been implicated in the pathogenesis of diverse conditions—including tissue injury, osteoarthritis, and malignancies—by modulating cellular proliferation, fundamental biological processes, and oxidative stress-induced inflammatory responses. The abdominal aorta was excised from rats, with tissue segments everted to reveal the endothelium. Cultured endothelial cells (ECs) were transfected with 100 nM hsa-miR-337-3p inhibitor. RNA sequencing was performed to map the genetic differences lining between the WT and miRNA-337-3p-/- EC.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE328540 | GEO | 2026/04/28

REPOSITORIES: GEO

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Project description:<p>Intracranial aneurysms (IAs) are benign cerebrovascular maladies characterized by pathological dilatation in the walls of intracranial arteries. However, spontaneous subarachnoid hemorrhage (SAH) resulting from aneurysm rupture poses a grave threat to the patient's life. Accumulating evidence implicates gut ecological dysregulation in the pathogenesis of IAs. Nevertheless, the relevance of gut dysbiosis to the rupture of IAs remains unknown. In this study, altogether 124 fecal samples were employed for microbiome sequencing by third-generation 16s rRNA sequencing, while 160 fecal samples were sequenced for metabolomics sequencing by liquid chromatography-mass spectroscopy techniques. Furthermore, the stool samples from IAs and healthy family controls were partitioned into two cohorts: the discovery set and the validation set for mutual cross-validation. Differential gut microbiota and metabolites associated with ruptured intracranial aneurysms (RIAs) were identified. Additionally, a superior risk assessment model for RIAs was constructed utilizing these differential species and metabolites. Subsequent integrated metabolomics and microbiomics analyses have uncovered a profound link between the dysregulation of unsaturated fatty acid and essential amino acid metabolic pathways and the rupture of IAs. This metabolic imbalance is attributed to alternations in the gut microbiota composition. Furthermore, we further revealed alterations in the gut flora of patients with IAs at high-risk rupture locations, incorporating the clinical characteristics. Finally, 30 peripheral blood and paired cerebrospinal fluid samples were tested to confirm variations in α-linolenic acid, linoleic acid and butyric acid concentrations among IA patients. This study underscores the crucial role of gut microbiota and metabolisms dysbiosis in IAs formation, while also highlighting a novel risk factor for aneurysm rupture. The identification and validation of differential species and metabolites provide new assessment biomarkers against IAs rupture.</p>

Project description:Background: Late-onset Alzheimer´s disease (LOAD) is a heterogeneous disorder influenced by complex genetic factors. We previously described intermediate alleles (IAs; 27-35 CAG repeats) in the huntingtin (HTT) gene as potential modifiers in around 6% of AD population. The caudate nucleus, the most affected region in Huntington's disease, is highly sensitive to these HTT CAG repeats. We hypothesized that HTT IAs induce gene expression deregulation, including altered microRNA (miRNA) profiles, leading to altered disease progression. Methods: We investigated the impact of HTT IAs on LOAD progression by genotyping HTT CAG repeats in a cohort of 323 LOAD patients and 335 healthy controls. Comprehensive histopathological and molecular analyses were performed on caudate nucleus samples from a matched subcohort (6 healthy controls, 14 LOAD non-HTT IA carriers, and 13 LOAD HTT IA carriers). Results: HTT IAs carriers patients exhibited decreased survival after disease onset compared to non-carriers. Histopathologically, while LOAD patients showed increased soluble HTT levels and altered tau pathology compared to controls, these changes were consistently and markedly exacerbated in HTT IA carriers. This phenotype was characterized by heightened diffuse HTT immunoreactivity and an advanced maturation of tau pathology, specifically a pronounced increase in neuronal tau 3R burden and 3R tau-enriched ghost tangles. Interestingly, this pathological state was associated with alterations in key splicing factors, including decreased SRSF6 levels and increased nuclear FUS-SFPQ complex assembly. Analysis of microRNA (miRNA) profiling in the caudate nucleus revealed that the LOAD-associated miRNA dysregulation was significantly amplified in HTT IA carriers, identifying a signature of five miRNAs (miR-100-5p, miR-218-5p, miR-27b-3p, miR-487-3p, and miR-9-3p). In silico modeling and target validation demonstrated that these miRNAs target components of the nuclear spliceosome machinery, such as SRSF family, along with MAPT and HTT genes, suggesting a direct link to the observed tauopathy. Conclusions: Our findings underscore that HTT IAs as critical modifiers in LOAD progression through an miRNA-mediated dysregulation of splicing and proteostasis. Thus, identifying HTT IAs through routine blood genetic screening offers a practical, non-invasive biomarker for patient stratification, taking a step forward to personalized therapeutic strategies in LOAD.

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Full length transcriptome sequencing of rat abdominal aorta primary EC

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