RESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the NR1H3 gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive. METHODS: Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified NR1H3 as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global Nr1h3-knockout and vascular smooth muscle cell-specific Nr1h3-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl2; 0.5 mol/L; 42 days). RESULTS: Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II- or CaCl2-treated mice. Global or vascular smooth muscle cell-specific Nr1h3 knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching. Uhrf1, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II- and CaCl2-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process. CONCLUSIONS: Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.
Asunto(s)
Aneurisma de la Aorta Abdominal , Proteínas Potenciadoras de Unión a CCAAT , Epigénesis Genética , Receptores X del Hígado , Ratones Noqueados , MicroARNs , Ubiquitina-Proteína Ligasas , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Animales , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Ratones , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Metilación de ADN , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Angiotensina II/farmacologíaRESUMEN
Glutamine (Gln), known as the most abundant free amino acid, is widely spread in human body. In this study, we demonstrated the protective effects of glutamine against mouse abdominal aortic aneurysm (AAA) induced by both angiotensin II (AngII) and calcium phosphate (Ca3(PO4)2) in vivo, which was characterized with lower incidence of mouse AAA. Moreover, histomorphological staining visually presented more intact elastic fiber and less collagen deposition in abdominal aortas of mice treated by glutamine. Further, we found glutamine inhibited the excessive production of reactive oxide species (ROS), activity of matrix metalloproteinase (MMP), M1 macrophage activation, and apoptosis of vascular smooth muscle cells (VSMCs) in suprarenal abdominal aortas of mice, what's more, the high expressions of MMP-2 protein, MMP-9 protein, pro-apoptotic proteins, and IL-6 as well as TNF-α in protein and mRNA levels in cells treated by AngII were down-regulated by glutamine. Collectively, these results revealed that glutamine protected against mouse AAA through inhibiting apoptosis of VSMCs, M1 macrophage activation, oxidative stress, and extracellular matrix degradation.
Asunto(s)
Angiotensina II , Aneurisma de la Aorta Abdominal , Apoptosis , Glutamina , Activación de Macrófagos , Músculo Liso Vascular , Miocitos del Músculo Liso , Estrés Oxidativo , Animales , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/prevención & control , Aneurisma de la Aorta Abdominal/metabolismo , Apoptosis/efectos de los fármacos , Ratones , Glutamina/farmacología , Angiotensina II/farmacología , Activación de Macrófagos/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Músculo Liso Vascular/citología , Humanos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Modelos Animales de Enfermedad , Masculino , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Aorta Abdominal/patología , Aorta Abdominal/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Fosfatos de CalcioRESUMEN
Recent studies confirmed that pyroptosis is involved in the progression of pulmonary hypertension (PH), which could promote pulmonary artery remodeling. Urolithin A (UA), an intestinal flora metabolite of ellagitannins (ETs) and ellagic acid (EA), has been proven to possess inhibitory effects on pyroptosis under various pathological conditions. However, its role on PH remained undetermined. To investigate the potential of UA in mitigating PH, mice were exposed to hypoxia (10% oxygen, 4 weeks) to induce PH, with or without UA treatment. Moreover, in vitro experiments were carried out to further uncover the underlying mechanisms. The in vivo treatment of UA suppressed the progression of PH via alleviating pulmonary remodeling. Pyroptosis-related genes were markedly upregulated in mice models of PH and reversed after the administration of UA. In accordance with that, UA treatment significantly inhibited hypoxia-induced pulmonary arterial smooth muscle cell (PASMC) pyroptosis via the AMPK/NF-κB/NLRP3 pathway. Our results revealed that UA treatment effectively mitigated PH progression through inhibiting PASMC pyroptosis, which represents an innovative therapeutic approach for PH.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Cumarinas , Hipertensión Pulmonar , Hipoxia , Miocitos del Músculo Liso , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Arteria Pulmonar , Piroptosis , Transducción de Señal , Animales , Cumarinas/farmacología , Cumarinas/uso terapéutico , Piroptosis/efectos de los fármacos , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Hipoxia/metabolismo , Hipoxia/complicaciones , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/etiología , Masculino , Proteínas Quinasas Activadas por AMP/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Recent advancements in cancer treatment have improved patient prognoses, but chemotherapy induced cardiotoxicity remains a prevalent concern. This study explores the potential of F-base-modified aptamers for targeted drug delivery, focusing on their impact on cardiotoxicity. From the phosphoramidite, F-base-functionalized Sgc8-F23 was prepared in an automated and programmable way, which was further reacted with paclitaxel (PTX) to give the F-base- modified aptamer Sgc8-paclitaxel conjugates (Sgc8-F23-PTX) efficiently. The conjugate exhibited prolonged circulation time and enhanced efficacy as a precision anticancer drug delivery system. Echocardiographic assessments revealed no exacerbation of cardiac dysfunction after myocardial infarction (MI) and no pathological changes or increased apoptosis in non-infarcted cardiac regions. Autophagy pathway analysis showed no discernible differences in Sgc8-F23-PTX-treated cardiomyocytes compared with controls, in contrast to the increased autophagy with nanoparticle albumin-bound-paclitaxel (Nab-PTX). Similarly, apoptosis analysis showed no significant differences. Moreover, Sgc8-F23-PTX exhibited no inhibitory effect on hERG, hNav1.5, or hCav1.2 channels. These findings suggest the safety and efficacy of F-base-modified Sgc8 aptamers for targeted drug delivery with potential clinical applications. Further research is warranted for clinical translation and exploration of other drug carriers.