Aneurysm severity is suppressed by deletion of CCN4.
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ABSTRACT:
SUBMITTER: Williams H
PROVIDER: S-EPMC8222476 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There is an unmet need for treatments to reduce abdominal aortic aneurysm (AAA) progression. Vascular smooth muscle cell (VSMC) apoptosis precipitates AAA formation, whereas VSMC proliferation repairs the vessel wall. We previously demonstrated that over-expression of EC4-Fc (truncated N-cadherin), or deletion of matrix-metalloproteinase-7 (Mmp-7) reduced VSMC apoptosis in mouse atherosclerotic plaques. Additionally, MMP-7 promotes VSMC apoptosis by cleavage of N-cadherin. We investigated their combined effect on AAA formation. Increased apoptosis and proliferation were observed in human AAA (HAAA) sections compared to normal aortae (HA). This coincided with increased MMP-7 activity and reduced N-cadherin protein levels in HAAA sections compared to HA. Using a mouse model of aneurysm formation, we showed that the combination of Mmp-7 deletion and EC4-Fc overexpression significantly increased AAA severity. Medial apoptosis and proliferation were both significantly reduced in these mice compared to control mice. In vitro, MMP-7 inhibition and EC4-Fc administration significantly supressed human aortic VSMC apoptosis (via activation of PI-3 kinase/Akt signalling) and proliferation. In conclusion, combined Mmp-7 deletion and systemic over-expression of EC4-Fc reduced both proliferation and apoptosis. Reduced proliferation-mediated repair over-rides any benefit of reduced apoptosis, increasing aneurysm severity. Future studies should therefore focus on retarding VSMC apoptosis whilst promoting VSMC proliferation.
| S-EPMC5725451 | biostudies-literature
Project description:KLF4 mediates inflammatory responses after vascular injury/disease; however, the role of KLF4 in abdominal aortic aneurysms (AAAs) remains unknown. The goals of the present study were to (1) determine the role of KLF4 in experimental AAA; and (2) determine the effect of KLF4 on smooth muscle (SM) cells in AAAs.KLF4 expression progressively increased at days 3, 7, and 14 after aortic elastase perfusion in C57BL/6 mice. Separately, loss of a KLF4 allele conferred AAA protection using ERTCre+ KLF4 flx/wt mice in the elastase AAA model. In a third set of experiments, SM-specific loss of 1 and 2 KLF4 alleles resulted in progressively greater protection using novel transgenic mice (MYHCre+ flx/flx, flx/wt, and wt/wt) in the elastase AAA model compared with control. Elastin degradation, MAC2, and cytokine production (MCP1, tumor necrosis factor-?, and interleukin-23) were significantly attenuated, whereas ?-actin staining was increased in KLF4 knockout mice versus controls. Results were verified in global KLF4 and SM-specific knockout mice using an angiotensin II model of aneurysm formation. KLF4 inhibition with siRNA attenuated downregulation of SM gene expression in vitro, whereas in vivo studies demonstrated that KLF4 binds to promoters of SM genes by chromatin immunoprecipitation analysis. Finally, human aortic aneurysms demonstrated significantly higher KLF4 expression that was localized to SM cells.KLF4 plays a critical role in aortic aneurysm formation via effects on SM cells. These results suggest that KLF4 regulates SM cell phenotypic switching and could be a potential therapeutic target for AAA disease.
| S-EPMC3922284 | biostudies-literature
Project description:Inadequate adaption to mechanical forces, including an elevated blood pressure, contributes to the development of arterial aneurysms. Recent studies have pointed to a mechano-protective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we created vascular SMC-specific knockouts (KOs) of YAP and TAZ using integrin-alpha8-Cre mice (i8-YT-KO). I8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within two weeks of knockout induction. Loss of YAP expression was also observed in human aortic aneurysms. I8-YT-KO mice developed vascular lesions in other arteries at later times, but the gastrointestinal tract was spared. Aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of proteoglycans and inflammatory cells, including macrophages and neutrophils. RNA-sequencing, proteomics, and myography demonstrated decreased contractile differentiation of SMCs and impaired vascular contractility. This associated with partial loss of vascular myocardin expression, reduced blood pressure, and edema. Mediators in the cGAS-STING pathway, which sparks inflammation in response to double-stranded DNA, were increased in aortic lysates. A sizeable increase of the transcription factor Sox9, along with several direct target genes, including aggrecan (Acan), contributed to proteoglycan accumulation. This was the earliest detectable change, occurring three days after knockout induction, and before the pro-inflammatory transition. In conclusion, Itga8-Cre deletion of YAP and TAZ represents a rapid and spontaneous aneurysm model that re-capitulates features of human abdominal aortic aneurysms.
2023-03-10 | MSV000091464 | MassIVE
Project description:Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 levels are increased in patients with thoracic aortic dissection (TAD). TAD shares several risk factors with abdominal aortic aneurysm (AAA). However, the role of ANGPTL8 in AAA pathogenesis has never been investigated. Here, we investigated the effect of ANGPTL8 knockout on abdominal aortic aneurysm (AAA) in ApoE-/- mice. ApoE-/-ANGPTL8-/- mice were generated by crossing ANGPTL8-/- and ApoE-/- mice. AAA was induced in ApoE-/- using perfusion of angiotensin II (AngII). ANGPTL8 was significantly upregulated in AAA tissues of human and experimental mice. Knockout of ANGPTL8 significantly reduced AngII-induced AAA formation, elastin breaks, aortic inflammatory cytokines, matrix metalloproteinase expression, and smooth muscle cell apoptosis in ApoE-/- mice. Similarly, ANGPTL8 sh-RNA significantly reduced AngII-induced AAA formation in ApoE-/- mice. ANGPTL8 deficiency inhibited AAA formation, and ANGPTL8 may therefore be a potential therapeutic target for AAA.
| S-EPMC10311111 | biostudies-literature
Project description:Testosterone is theorized to play a major role in the pathophysiology of abdominal aortic aneurysms (AAAs) because this disease occurs primarily in men. The role of the androgen receptor (AR) in the formation of AAAs has not been well elucidated, and therefore, it is hypothesized that androgen blockade will attenuate experimental aortic aneurysm formation.Aortas of 8- to 12-week-old male C57Bl/6 wild-type (WT) mice or male AR knockout (AR(-/-)) mice were perfused with purified porcine pancreatic elastase (0.35 U/mL) to induce AAA formation. Two groups of WT male mice were treated with the AR blockers flutamide (50 mg/kg) or ketoconazole (150 mg/kg) twice daily by intraperitoneal injection. Aortas were harvested on day 14 after video micrometry was used to measure AAA diameter. Cytokine arrays and histologic analysis were performed on aortic tissue. Groups were compared using an analysis of variance and a Tukey post hoc test.Flutamide and ketoconazole treatment (mean ± standard error of the mean) attenuated AAA formation in WT mice (84.2% ± 22.8% [P = .009] and 91.5% ± 18.2% [P = .037]) compared with WT elastase (121% ± 5.23%). In addition, AR(-/-) mice showed attenuation of AAA growth (64.4% ± 22.7%; P < .0001) compared with WT elastase. Cytokine arrays of aortic tissue revealed decreased levels of proinflammatory cytokines interleukin (IL)-?, IL-6, and IL-17 in flutamide-treated and AR(-/-) groups compared with controls.Pharmacologic and genetic AR blockade cause attenuation of AAA formation. Therapies for AR blockade used in prostate cancer may provide medical treatment to halt progression of AAAs in humans.
| S-EPMC4884130 | biostudies-literature
Project description:ObjectivesPreviously, we have shown the involvement of cellular communication network factor 4/Wnt-activated protein Wnt-1-induced signaling protein 1 (CCN4/WISP1) in osteoarthritic (OA) cartilage and its detrimental effects on cartilage. Here, we investigated characteristics of CCN4 in chondrocyte biology by exploring correlations of CCN4 with genes expressed in human OA cartilage with functional follow-up.DesignSpearman correlation analysis was performed for genes correlating with CCN4 using our previously established RNA sequencing dataset of human preserved OA cartilage of the RAAK study, followed by a pathway enrichment analysis for genes with ρ ≥|0.6.| Chondrocyte migration in the absence or presence of CCN4 was determined in a scratch assay, measuring scratch size using a live cell imager for up to 36 h. Changes in expression levels of 12 genes, correlating with CCN4 and involved in migratory processes, were determined with reverse transcription-quantitative polymerase chain reaction (RT-qPCR).ResultsCorrelation of CCN4 with ρ ≥|0.6| was found for 58 genes in preserved human OA cartilage. Pathway analysis revealed "neural crest cell migration" as most significant enriched pathway, containing among others CORO1C, SEMA3C, and SMO. Addition of CCN4 to primary chondrocytes significantly enhance chondrocyte migration as demonstrated by reduced scratch size over the course of 36 h, but at the timepoints measured no effect was observed on mRNA expression of the 12 genes.ConclusionCCN4 increases cell migration of human primary OA chondrocytes. Since WISP1 expression is known to be increased in OA cartilage, this may serve to direct chondrocytes toward cartilage defects and orchestrate repair.
| S-EPMC10076902 | biostudies-literature
Project description:In the present study, we want to test whether deletion of resistin-like molecule-beta (RELM?) attenuates angiotensin II (Ang II)-induced formation of abdominal aortic aneurysm (AAA). RELM? gene expression was inhibited by siRNA both in vivo and in vitro. Apolipoprotein E-knockout (ApoE-/-) mice were randomly divided into saline, Ang II, siRNA negative control (si-NC) and siRNA RELM? (si-RELM?) groups (n=15 each), and mice in the last three groups underwent Ang II infusion for 4 weeks to induce AAA. RELM? gene deficiency significantly decreased AAA incidence and severity, which was associated with reduced macrophage accumulation and decreased expression of proinflammatory cytokines (monocyte chemoattractant protein 1 and interleukin 6), matrix metalloproteinase 2 (MMP-2) and MMP-9 in the aortic wall. In cultured macrophages, RELM? deficiency blunted the response of macrophages to Ang II and downregulated the levels of proinflammatory cytokines, MMP-2 and MMP-9. Recombinant RELM? promoted the secretion of proinflammatory cytokines, MMP-2 and MMP-9 in macrophages and activated extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) signaling, which was reversed with pretreatment with inhibitors of ERK1/2 and JNK. Deletion of RELM? attenuated Ang II-induced AAA formation in ApoE-/- mice. The inherent mechanism may involve the reduced expression of proinflammatory cytokines, MMP-2 and MMP-9, which was mediated by ERK1/2 and JNK activation. Therefore, inhibiting RELM? secretion may be a novel approach for anti-aneurysm treatment.
| S-EPMC5732796 | biostudies-literature
Project description:ObjectiveRecent studies have highlighted socioeconomic disparities in the severity and management of abdominal aortic aneurysm (AAA) disease. However, these studies focus on individual measures of social disadvantage such as income and insurance status. The area deprivation index (ADI), a validated measure of neighborhood deprivation, provides a more comprehensive assessment of social disadvantage. Therefore, we examined the impact of ADI on AAA severity and its management.MethodsWe identified all patients who underwent endovascular or open repair of an AAA in the Vascular Quality Initiative registry between 2003 and 2020. An ADI score of 1 to 100 was assigned to each patient based on their residential zip code, with higher ADI scores corresponding with increasing deprivation. Patients were categorized by ADI quintiles. Outcomes of interest included rates of ruptured AAA (rAAA) repair versus an intact AAA repair and rates of endovascular repair (EVAR) versus the open approach. Logistic regression was used to evaluate for an independent association between ADI quintile and these outcomes.ResultsAmong 55,931 patients who underwent AAA repair, 6649 (12%) were in the lowest ADI quintile, 11,692 (21%) in the second, 15,958 (29%) in the third, 15,035 (27%) in the fourth, and 6597 (12%) in the highest ADI quintile. Patients in the two highest ADI quintiles had a higher proportion of rAAA repair (vs intact repair) compared with those in the lowest ADI quintile (8.8% and 9.1% vs 6.2%; P < .001). They were also less likely to undergo EVAR (vs open approach) when compared with the lowest ADI quintile (81% and 81% vs 88%; P < .001). There was an overall trend toward increasing rAAA and decreasing EVAR rates with increasing ADI quintiles (P < .001). In adjusted analyses, when compared with patients in the lowest ADI quintile, patients in the highest ADI quintile had higher odds of rAAA repair (odds ratio, 1.4; 95% confidence interval, 1.2-1.8; P < .001) and lower odds of undergoing EVAR (odds ratio, 0.54; 95% confidence interval, 0.45-0.65; P < .001).ConclusionsAmong patients who underwent AAA repair in the Vascular Quality Initiative, those with higher neighborhood deprivation had significantly higher rates of rAAA repair (vs intact repair) and lower rates of EVAR (vs open approach). Further work is needed to better understand neighborhood factors that are contributing to these disparities to identify community-level targets for improvement.
| S-EPMC10038823 | biostudies-literature
Project description:CCN proteins are secreted into the extracellular environment where they interact with both components of the extracellular matrix and with cell surface receptors to regulate cellular function. Through these interactions, CCNs act as extracellular ligands to activate intracellular signal transduction pathways. CCN4/WISP-1, like other CCNs, plays multiple physiologic roles in development and also participates in pathogenesis. CCN4 is of particular interest with respect to cancer, showing promise as a biomarker or prognostic factor as well as a potential therapeutic target. This review focuses on recent work addressing the role of CCN4 in cancer. While CCN4 has been identified as an oncogene in a number of cancers, where it enhances cell migration and promoting epithelial-mesenchymal transition, there are other cancers where CCN4 appears to play an inhibitory role. The mechanisms underlying these differences in cellular response have not yet been delineated, but are an active area of investigation. The expression and activities of CCN4 splice variants are likewise an emerging area for study. CCN4 acts as an autocrine factor that regulates the cancer cells from which it is secreted. However, CCN4 is also a paracrine factor that is secreted by stromal fibroblasts, and can affect the function of vascular endothelial cells. In summary, current evidence is abundant in regard to establishing potential roles for CCN4 in oncogenesis, but much remains to be learned about the functions of this fascinating protein as both an autocrine and paracrine regulator in the tumor microenvironment.
| S-EPMC6118280 | biostudies-literature
Project description:WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the CCN family able to mediate cell growth, transformation and survival in a tissue-specific manner. Here, we report that WISP1 expression was highly increased in preadipocytes and decreased during adipocyte differentiation. Moreover, we observed an increase in WISP1 gene expression in adipose tissue from both diet-induced and leptin-deficient ob/ob obese mice, suggesting that WISP1 could be involved in the pathophysiological onset of obesity. Interestingly, overexpression of WISP1 in 3T3-F442A cells prevented adipocyte differentiation via downregulation of peroxisome proliferator-activated receptor (PPARγ) transcriptional activity thereby attenuating the expression of adipogenic markers. Conversely, silencing of WISP1 enhanced adipocyte differentiation. We further show that the inactivation of PPARγ transcriptional activity was mediated, at least in part, by a direct physical association between WISP1 and PPARγ, followed by proteasome-dependent degradation of PPARγ. These results suggest for the first time that WISP1 interacts with PPARγ and that this interaction results in the inhibition of PPARγ activity. Taken together our results suggest that WISP1 functions as a negative regulator of adipogenesis.
| S-EPMC5431985 | biostudies-literature