Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms.
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ABSTRACT:
SUBMITTER: Davis FM
PROVIDER: S-EPMC8008365 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abdominal aortic aneurysm (AAA), characterized by a localized dilation of the abdominal aorta, is a life-threatening vascular pathology. Because of the current lack of effective treatment for AAA rupture, prevention is of prime importance for AAA management. Calorie restriction (CR) is a nonpharmacological intervention that delays the aging process and provides various health benefits. However, whether CR prevents AAA formation remains untested. In this study, we subjected Apoe-/- mice to 12 wk of CR and then examined the incidence of angiotensin II (AngII)-induced AAA formation. We found that CR markedly reduced the incidence of AAA formation and attenuated aortic elastin degradation in Apoe-/- mice. The expression and activity of Sirtuin 1 (SIRT1), a key metabolism/energy sensor, were up-regulated in vascular smooth muscle cells (VSMCs) upon CR. Importantly, the specific ablation of SIRT1 in smooth muscle cells abolished the preventive effect of CR on AAA formation in Apoe-/- mice. Mechanistically, VSMC-SIRT1-dependent deacetylation of histone H3 lysine 9 on the matrix metallopeptidase 2 (Mmp2) promoter was required for CR-mediated suppression of AngII-induced MMP2 expression. Together, our findings suggest that CR may be an effective intervention that protects against AAA formation.
| S-EPMC5068228 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA), commonly occurring in the aged population, is a degenerative disease that dilate and weaken infrarenal aorta due to progressive degeneration of aortic wall integrity. Vinpocetine, a derivative of alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment in the aged population. Recent studies have indicated that vinpocetine antagonizes occlusive vascular disorders such as intimal hyperplasia and atherosclerosis. However, its role in vascular degenerative disease AAA remains unexplored. Herein, we determined the effect of vinpocetine on the formation of AAA as well as the intervention of pre-existing moderate AAA. AAA was induced by periaortic elastase application in C57BL/6J mice. Systemic vinpocetine treatment was applied daily via intraperitoneal injection. We showed that vinpocetine pre-treatment remarkably attenuated aneurysmal dilation assessed by diameter and volume. More importantly, vinpocetine also significantly suppressed the progression of pre-existing moderate AAA in a post-intervention model. Vinpocetine improved multiple cellular and molecular changes associated with AAA, such as elastin degradation, media smooth muscle cell depletion, collagen fibers remodeling and macrophage infiltration in aneurysmal tissues. Vinpocetine potently suppressed tumor necrosis factor-α-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation and proinflammatory mediator expression in primary cultured macrophages in vitro, as well as in the aorta wall in vivo, suggesting vinpocetine conferred anti-AAA effect at least partially via the inhibition of inflammation. Taken together, our findings reveal a novel role of vinpocetine in AAA formation, development and progression. Given the excellent safety profile of vinpocetine, the present study suggests vinpocetine may be a novel therapeutic agent for AAA prevention and treatment.
| S-EPMC7720778 | biostudies-literature
Project description:Osteoarthritis (OA) is a prevalent joint disease with no effective treatment strategies. Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis. Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies, the epigenetic control of OA remains unclear. Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes, including cell differentiation, proliferation, autophagy, and apoptosis. However, the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown. In this work, we confirmed the upregulation of JMJD3 in aberrant force-induced cartilage injury in vitro and in vivo. Functionally, inhibition of JMJD3 by its inhibitor, GSK-J4, or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury. Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression. Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis, cartilage degeneration, extracellular matrix degradation, and inflammatory responses. In vivo, anterior cruciate ligament transection (ACLT) was performed to construct an OA model, and the therapeutic effect of GSK-J4 was validated. More importantly, we adopted a peptide-siRNA nanoplatform to deliver si-JMJD3 into articular cartilage, and the severity of joint degeneration was remarkably mitigated. Taken together, our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression. Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-siRNA nanocomplexes.
| S-EPMC9279410 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is a life-threatening disease characterized by an inflammatory macrophage phenotype that contributes to pathological vascular remodeling. Although the mechanisms regulating macrophage-mediated inflammation during AAA development remain undefined, accumulating evidence suggests that epigenetic alterations play a critical role. Here using single cell RNA-sequencing techniques, we identify that the histone demethylase JMJD3 is elevated in human AAA monocytes/macrophages, resulting in the upregulation of cellular activation and a proinflammatory immune response.
2021-02-13 | GSE166676 | GEO
Project description:Complement system, an innate immunity, has been well documented to play a critical role in many inflammatory diseases. However, the role of complement in the pathogenesis of abdominal aortic aneurysm, which is considered an immune and inflammatory disease, remains obscure.Here, we evaluated the pathogenic roles of complement membrane attack complex and CD59, a key regulator that inhibits the membrane attack complex, in the development of abdominal aortic aneurysm. We demonstrated that in the angiotensin II-induced abdominal aortic aneurysm model, deficiency of the membrane attack complex regulator CD59 in ApoE-null mice (mCd59ab(-/-)/ApoE(-/-)) accelerated the disease development, whereas transgenic overexpression of human CD59 (hCD59(ICAM-2+/-)/ApoE(-/-)) in this model attenuated the progression of abdominal aortic aneurysm. The severity of aneurysm among these 3 groups positively correlates with C9 deposition, and/or the activities of MMP2 and MMP9, and/or the levels of phosphorylated c-Jun, c-Fos, IKK-alpha/beta, and p65. Furthermore, we demonstrated that the membrane attack complex directly induced gene expression of matrix metalloproteinase-2 and -9 in vitro, which required activation of the activator protein-1 and nuclear factor-kappaB signaling pathways.Together, these results defined the protective role of CD59 and shed light on the important pathogenic role of the membrane attack complex in abdominal aortic aneurysm.
| S-EPMC3057574 | biostudies-literature
Project description:An abdominal aortic aneurysm (AAA) is a progressive aortic dilation that may lead to rupture, which is usually lethal. This study identifies the state of failure in the resolution of inflammation by means of decreased expression of the pro-resolving receptor A lipoxin/formyl peptide receptor 2 (ALX/FPR2) in the adventitia of human AAA lesions. Mimicking this condition by genetic deletion of the murine ALX/FPR2 ortholog in hyperlipidemic mice exacerbated the aortic dilation induced by angiotensin II infusion, associated with decreased vascular collagen and increased inflammation. The authors also identified key roles of lipoxin formation through 12/15-lipoxygenase and neutrophil p38 mitogen-activated protein kinase. In conclusion, this study established pro-resolving signaling by means of the ALX/FPR2 receptor in aneurysms and vascular inflammation.
| S-EPMC6314955 | biostudies-literature
Project description:Background Abdominal aortic aneurysms (AAA) are characterized by vascular inflammation and remodeling that can lead to aortic rupture resulting in significant mortality. Pannexin-1 channels on endothelial cells (ECs) can modulate ATP secretion to regulate the pathogenesis of AAA formation. Our hypothesis focused on potential of spironolactone to inhibit EC-mediated ATP release for the mitigation of AAA formation. Methods A topical elastase AAA model was used initially in C57BL/6 (wild-type; WT) male mice. Mice were administered either a vehicle control (saline) or spironolactone and analyzed on day 14. In a second chronic AAA model, mice were subjected to elastase and β-aminopropionitrile (BAPN) treatment with/without administration of spironolactone to pre-formed aneurysms starting on day 14 and analyzed on day 28. Aortic diameter was evaluated by video micrometry and aortic tissue was analyzed for cytokine expression and histology. ATP measurement and matrix metalloproteinase (MMP2) activity was evaluated in aortic tissue on days 14 or -28. In vitro studies were performed to evaluate the crosstalk between aortic ECs with macrophages or smooth muscle cells. Results In the elastase AAA model, spironolactone treatment displayed a significant decrease in aortic diameter compared to elastase-treated controls on day 14. A significant increase in smooth muscle α-actin expression as well as decrease in elastic fiber disruption and immune cell (macrophages and neutrophils) infiltration was observed in mice treated with spironolactone compared to saline-treated controls. Spironolactone treatment also significantly mitigated pro-inflammatory cytokine expression, MMP2 activity and ATP content in aortic tissue compared to controls. Moreover, in the chronic AAA model, spironolactone treatment of pre-formed aneurysms significantly attenuated vascular inflammation and remodeling to attenuate the progression of AAAs compared to controls. Mechanistically, in vitro data demonstrated that spironolactone treatment attenuates extracellular ATP release from endothelial cells to mitigate macrophage activation (IL-1β and HMGB1 expression) and smooth muscle cell-dependent vascular remodeling (MMP2 activity). Conclusion These results demonstrate that spironolactone can mitigate aortic inflammation and remodeling to attenuate AAA formation as well as decrease growth of pre-formed aneurysms via inhibition of EC-dependent ATP release. Therefore, this study implicates a therapeutic application of spironolactone in the treatment of AAAs.
| S-EPMC9908993 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is a life-threatening degenerative vascular disease. Endothelial cell (EC) dysfunction is implicated in AAA. Our group recently demonstrated that Krüppel-like factor 11 (KLF11) plays an essential role in maintaining vascular homeostasis, at least partially through inhibition of EC inflammatory activation. However, the functions of endothelial KLF11 in AAA remain unknown. Here we found that endothelial KLF11 expression was reduced in the ECs from human aneurysms and was time dependently decreased in the aneurysmal endothelium from both elastase- and Pcsk9/AngII-induced AAA mouse models. KLF11 deficiency in ECs markedly aggravated AAA formation, whereas EC-selective KLF11 overexpression markedly inhibited AAA formation. Mechanistically, KLF11 not only inhibited the EC inflammatory response but also diminished MMP9 expression and activity and reduced NADPH oxidase 2-mediated production of reactive oxygen species in ECs. In addition, KLF11-deficient ECs induced smooth muscle cell dedifferentiation and apoptosis. Overall, we established endothelial KLF11 as a potentially novel factor protecting against AAA and a potential target for intervention in aortic aneurysms.
| S-EPMC8021107 | biostudies-literature
Project description:Allergic asthma with high plasma IgE levels is a significant risk factor of human abdominal aortic aneurysm (AAA). This study tests a direct role of IgE in angiotensin-II (Ang-II) perfusion- and peri-aortic CaCl2 injury-induced AAA in mice. In both models, IgE-deficiency in Apoe-/- Ige-/- mice blunts AAA growth and reduces lesion accumulation of macrophages, CD4+ and CD8+ T cells, and lesion MHC class-II expression, CD31+ microvessel growth, and media smooth muscle cell loss, compared with those from Apoe-/- control mice. Real time-PCR reveals significant reductions in expression of neutrophil chemoattractants MIP-2α and CXCL5 in AAA lesions or macrophages from Apoe-/- Ige-/- mice, along with reduced lesion Ly6G+ neutrophil accumulation. Consistent with reduced lesion inflammatory cell accumulation, we find significant reductions of plasma and AAA lesion IL6 expression in Apoe-/- Ige-/- mice. Immunofluorescent staining and FACS analysis show that AAA lesion neutrophils express FcεR1. Mechanistic study demonstrates that IgE induces neutrophil FcεR1 expression, activates MAPK signaling, and promotes IL6 production. This study supports a direct role of IgE in AAA by promoting lesion chemokine expression, inflammatory cell accumulation, MAPK signaling, and cytokine expression. IgE inhibition may represent a novel therapeutic approach in AAA management.
| S-EPMC7018578 | biostudies-literature
Project description:Current clinical practice for the assessment of abdominal aortic aneurysms (AAA) is based on vessel diameter and does not account for the multifactorial, heterogeneous remodeling that results in the regional weakening of the aortic wall leading to aortic growth and rupture. This study was conducted to determine correlation between a novel non-invasive surrogate measure of regional aortic weakening and the results from invasive analyses performed on corresponding ex vivo aortic samples. Tissue samples were evaluated to classify local wall weakening and likelihood of further degeneration based on non-invasive indices. A combined, image-based fluid dynamic and in-vivo strain analysis approach was used to estimate the Regional Aortic Weakness (RAW) index and assess individual aortas of AAA patients prior to elective surgery. Nine patients were treated with complete aortic resection allowing the systematic collection of tissue samples that were used to determine regional aortic mechanics, microstructure and gene expression by means of mechanical testing, microscopy and transcriptomic analyses. The RAW index was significantly higher for samples exhibiting lower mechanical strength (p = 0.035) and samples classified with low elastin content (p = 0.020). Samples with higher RAW index had the greatest number of genes differentially expressed compared to any constitutive metric. High RAW samples showed a decrease in gene expression for elastin and a down-regulation of pathways responsible for cell movement, reorganization of cytoskeleton, and angiogenesis. Please note that the sample 'characteristisc: strain' represents the in-vivo strain corresponding to each section of aorta, which is measured from dynamic CT images of patient AAA using a proprietary software.
2021-01-26 | GSE165470 | GEO