Inhibition of microRNA-33b specifically ameliorates abdominal aortic aneurysm formation via suppression of inflammatory pathways
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ABSTRACT:
SUBMITTER: Yamasaki T
PROVIDER: S-EPMC9283493 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abdominal aortic aneurysm (AAA) represents the serious vascular degenerative disorder, which causes high incidence and mortality. Alpha-ketoglutarate (AKG), a crucial metabolite in the tricarboxylic acid (TCA) cycle, has been reported to exert significant actions on the oxidative stress and inflammation. However, its role in AAA still remains elusive. Herein, we examined the effects of AKG on the formation of AAA. The study established an elastase-induced mouse abdominal aortic aneurysms model as well as a TNF-α-mediated vascular smooth muscle cells (VSMCs) model, respectively. We displayed that AKG pre-treatment remarkably prevented aneurysmal dilation assessed by diameter and volume and reduced aortic rupture. In addition, it was also observed that AKG treatment suppressed the development of AAA by attenuating the macrophage infiltration, elastin degradation and collagen fibers remodeling. In vitro, AKG potently decreased TNF-α-induced inflammatory cytokines overproduction, more apoptotic cells and excessive superoxide. Mechanistically, we discovered that upregulation of vpo1 in AAA was significantly suppressed by AKG treatment. By exploring the RNA-seq data, we found that AKG ameliorates AAA mostly though inhibiting oxidative stress and the inflammatory response. PXDN overexpression neutralized the inhibitory effects of AKG on ROS generation and inflammatory reaction in MOVAS. Furthermore, AKG treatment suppressed the expression of p-ERK1/2, 3-Cl Tyr in vivo and in vitro. ERK activator disrupted the protective of AKG on TNF-α-induced VSMCs phenotypic switch. Conclusively, AKG can serve as a beneficial therapy for AAA through regulating PXDN/HOCL/ERK signaling pathways.
| S-EPMC9548204 | biostudies-literature
Project description:We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach.Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I(2) = 70%, P = 1.1 × 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I(2) = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers.A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.
| S-EPMC3869968 | biostudies-literature
Project description:Abdominal artery aneurysm (AAA) refers to abdominal aortic dilatation of 3 cm or greater. AAA is frequently underdiagnosed due to often asymptomatic character of the disease, leading to elevated mortality due to aneurysm rupture. MiRNA constitute a pool of small RNAs controlling gene expression and is involved in many pathologic conditions in human. Targeted panel detecting altered expression of miRNA and genes involved in AAA would improve early diagnosis of this disease. In the presented study, we selected and analyzed miRNA and gene expression signatures in AAA patients. Next, generation sequencing was applied to obtain miRNA and gene-wide expression profiles from peripheral blood mononuclear cells in individuals with AAA and healthy controls. Differential expression analysis was performed using DESeq2 and uninformative variable elimination by partial least squares (UVE-PLS) methods. A total of 31 miRNAs and 51 genes were selected as the most promising biomarkers of AAA. Receiver operating characteristics (ROC) analysis showed good diagnostic ability of proposed biomarkers. Genes regulated by selected miRNAs were determined in silico and associated with functional terms closely related to cardiovascular and neurological diseases. Proposed biomarkers may be used for new diagnostic and therapeutic approaches in management of AAA. The findings will also contribute to the pool of knowledge about miRNA-dependent regulatory mechanisms involved in pathology of that disease.
| S-EPMC7355415 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is increasing due to aging of the population and is a major cause of death among the elderly. Ultrasound screening programs are useful in early diagnosis, but aneurysm size is not always a good predictor of rupture. Our aim was to analyze the value of circulating molecules related to oxidative stress and inflammation as new biomarkers to assist the management of AAA. The markers were quantified by ELISA, and their expression in the aneurysmal wall was studied by real-time PCR and by immunostaining. Correlation analysis of the studied markers with aneurysm diameter and peak wall stress (PWS), obtained by finite element analysis, and multivariate regression analysis to assess potential confounding factors were performed. Our study shows an extensive inflammatory infiltration in the aneurysmal wall, mainly composed by T-cells, macrophages and B-cells and altered levels of reactive oxygen species (ROS), IgM, IgG, CD38, GDF15, S100A4 and CD36 in plasma and in the aneurysmal tissue of AAA patients compared with controls. Circulating levels of IgG, CD38 and GDF15 positively correlated with abdominal aortic diameter, and CD38 was correlated with PWS. Our data show that altered levels of IgG, CD38 and GDF15 have potential diagnostic value in the assessment of AAA.
| S-EPMC8070751 | biostudies-literature
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.
| S-EPMC3266800 | biostudies-other
Project description:MicroRNAs (miRNAs) are deregulated in various vascular ailments including abdominal aortic aneurysm (AAA). MiR-103 is involved in vascular, metabolic, and malignant diseases, but whether it participates in the pathogenesis of AAA remains elusive. ADAM10 plays a vital role in the formation of aneurysm, but whether miRs modulate its activity during AAA formation is totally unknown. In this study, we detected the significantly increased protein expression of ADAM10 in angiotensin II induced murine AAA specimens, while the mRNA expression of ADAM10 was similar between AAA and control, suggesting the posttranscriptional regulation. The ADAM10 specific inhibitor GI254023X dramatically reduced the macrophage infiltration of murine abdominal aorta. Bioinformatic predictions suggest that ADAM10 is the target of miR-103a/107 but the binding site is exclusive. At the cellular level, miR-103a-1 suppressed the protein expression of ADAM10, while antisense miR-103a-1 increased its expression. Particularly, with the progression of murine AAA, the mRNA expression of miR-103a/107 substantially decreased and the protein expression of ADAM10 greatly increased. Together, our data afford the new insight that miR-103a inhibited AAA growth via targeting ADAM10, which might be a promising therapeutic strategy to alleviate AAA.
| S-EPMC5357520 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti-inflammatory properties by inhibiting nuclear factor ?-light-chain-enhancer of activated B cells (NF-?B) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 ± 15.85% vs. 90.62 ± 22.91%, P < 0.05). Immunohistochemistry analyses revealed that Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-?B activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor ?, and interferon-?] in the treated aortae. Furthermore, Andro suppressed ?4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-?B-mediated cytokine production and ?4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms.
| S-EPMC4702070 | biostudies-literature
Project description:Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid-modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.
| S-EPMC5753594 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since the first candidate gene studies were published 20 years ago, approximately 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. These studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, only when appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called contactin-3, which is located on chromosome 3p12.3. However, two follow-up studies could not replicate this association. Two other SNPs, which are located on chromosome 9p21 and 9q33, were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense ribonucleic acid that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute toward AAA pathogenesis.
| S-EPMC3058859 | biostudies-literature
Project description:Background Development of abdominal aortic aneurysm (AAA) is associated with proinflammatory cytokines including interleukin-12 (IL12). Deficiency of interleukin 12p40 (IL12p40) increases localized fibrotic events by promoting TGFβ2 (transforming growth factor β)-dependent anti-inflammatory response. Here, we determined whether IL12p40 deficiency in apolipoprotein E-/- mice attenuates the development of AAA by antagonizing proinflammatory response. Methods and Results Double knockout (DKO) mice were generated by crossbreeding IL12p40-/- mice with apolipoprotein E-/- mice (n=12). Aneurysmal studies were performed using angiotensin II (1 µg/kg/min; subcutaneous). Surprisingly, DKO mice did not prevent the development of AAA with angiotensin II infusion. Immunohistological analysis, however, showed distinct pathological features between apolipoprotein E-/- and DKO mice. Polymerase chain reaction (7 day) and cytokine arrays (28 day) of the aortic tissues from DKO mice showed significantly increased expression of cytokines related to anti-inflammatory response (interleukin 5 and interleukin 13), synthetic vascular smooth muscle cell phenotype (Activin receptor-like kinase-1 (ALK-1), artemin, and betacellulin) and T helper 17-associated response (4-1BB, interleukin-17e (Il17e) and Cd40 ligand (Cd-40L)). Indeed, DKO mice exhibited increased expression of the fibro-proteolytic pathway in the medial layer of aortae induced by cellular communication network factor 2 (CCN2) and Cd3+IL17+ cells compared with apolipoprotein E-/- mice. Laser capture microdissection showed predominant expression of CCN2/TGFβ2 in the medial layer of human AAA. Finally, Ccn2 haploinsufficiency in the mice showed decreased AAA incidence in response to elastase infusion, associated with decreased matrix metalloproteinase-2 expression. Conclusions Our study reveals novel roles for IL12p40 deficiency in inducing fibro-proteolytic activities in the aneurysmal mouse model. Mechanistically, these effects of IL12p40 deficiency are mediated by CCN2/matrix metalloproteinase-2 crosstalk in the medial layer of aneurysmal aortae.
| S-EPMC7955443 | biostudies-literature