Sildenafil (Viagra) Aggravates the Development of Experimental Abdominal Aortic Aneurysm.
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SUBMITTER: Zhang C
PROVIDER: S-EPMC9238513 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined.Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening precedes aneurysm growth. Finite-element analysis reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with the reduced segmental stiffness of the AAA-prone aorta (attributable to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species, attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, and attenuated apoptosis within the aortic wall, as well. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening.The present study introduces the novel concept of segmental aortic stiffening as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring segmental aortic stiffening may aid the identification of patients at risk for AAA.
| S-EPMC4439288 | biostudies-literature
Project description:Abstract: The pathogenesis of AAA involves vascular inflammation and oxidative stress. Astragali Radix contains cycloastragenol (CAG) known to have anti-inflammatory and anti-oxidative properties. We hypothesized that CAG supplement impairs AAA progression. AAA was induced in male rats by intraluminal elastase infusion in the infrarenal aorta and treated daily with CAG (125 mg/kg/day). Aortic expansion was followed weekly by ultrasound, with euthanization at day 28. Changes in AAA wall composition were analyzed at mRNA levels, histology, zymography and explorative proteomic analyses. At day 28, mean AAA diameter was 37% lower in CAG group (p<0.0001). In aneurysm cross sections, elastin content was insignificantly higher in CAG group (10.5% ± 5.9% vs 19.9% ± 16.8%, p=0.20) with more preserved elastin lamellae structures (p=0.0003) and with no microcalcifications. Aneurysmal matrix metalloprotease-2 activity was reduced by CAG treatment (p=0.022), and mRNA levels of inflammatory- and antioxidative markers showed no difference between groups. Explorative proteomic analysis showed no difference in protein levels when adjustment for multiple testing. Amongst unadjusted affected proteins were fibulin-5 (p=0.02), aquaporin-1 (p=0.02) and prostacyclin synthase (p=0.006). CAG impairs experimental AAA progression by reduction of elastin degradation through decreased MMP-2 activity, thus CAG could be considered tested in AAA patients.
2022-05-20 | PXD030441 | Pride
Project description:The pathogenesis of abdominal aortic aneurysm involves vascular inflammation and elastin degradation. Astragalusradix contains cycloastragenol, which is known to be anti-inflammatory and to protect against elastin degradation. We hypothesized that cycloastragenol supplementation inhibits abdominal aortic aneurysm progression. Abdominal aortic aneurysm was induced in male rats by intraluminal elastase infusion in the infrarenal aorta and treated daily with cycloastragenol (125 mg/kg/day). Aortic expansion was followed weekly by ultrasound for 28 days. Changes in aneurysmal wall composition were analyzed by mRNA levels, histology, zymography and explorative proteomic analyses. At day 28, mean aneurysm diameter was 37% lower in the cycloastragenol group (p < 0.0001). In aneurysm cross sections, elastin content was insignificantly higher in the cycloastragenol group (10.5% ± 5.9% vs. 19.9% ± 16.8%, p = 0.20), with more preserved elastin lamellae structures (p = 0.0003) and without microcalcifications. Aneurysmal matrix metalloprotease-2 activity was reduced by the treatment (p = 0.022). Messenger RNA levels of inflammatory- and anti-oxidative markers did not differ between groups. Explorative proteomic analysis showed no difference in protein levels when adjusting for multiple testing. Among proteins displaying nominal regulation were fibulin-5 (p = 0.02), aquaporin-1 (p = 0.02) and prostacyclin synthase (p = 0.007). Cycloastragenol inhibits experimental abdominal aortic aneurysm progression. The suggested underlying mechanisms involve decreased matrix metalloprotease-2 activity and preservation of elastin and reduced calcification, thus, cycloastragenol could be considered for trial in abdominal aortic aneurysm patients.
| S-EPMC8962318 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain-containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell-specific (VSMC-specific) Prdm16-knockout (Prdm16SMKO) mice already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes, including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase that can degrade various ECMs. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment.
| S-EPMC10393233 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain–containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell–specific (VSMC-specific) Prdm16-knockout (Prdm16SMKO) mice already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes, including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase that can degrade various ECMs. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment.
2023-06-08 | GSE222440 | GEO
Project description:BACKGROUND:Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. METHODS:We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient ( ApoE-/-) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. RESULTS:Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1? as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1? and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1? via recruiting the transcription factor specificity protein 1 to the promoter region. CONCLUSIONS:The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.
| S-EPMC6193867 | biostudies-literature
Project description:Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1? (MIP-1?) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.
| S-EPMC5828611 | biostudies-literature
Project description:Background Integrin αM (CD11b), which is encoded by the Integrin Subunit Alpha M (ITGAM) gene, is not only a surface marker of monocytes but also an essential adhesion molecule. In this study, we investigated the effect of CD11b on experimental abdominal aortic aneurysm and the potential underlying mechanisms. Methods and Results The incidence of abdominal aortic aneurysm was not significantly lower in ITGAM(-/-) mice than in control mice. Nevertheless, knockout of CD11b reduced the maximum abdominal aortic diameter, macrophage infiltration, matrix metalloproteinase-9 expression, and elastin and collagen degradation. Additionally, lower expression of IL-6 was found in both the peripheral blood and abdominal aortas of ITGAM(-/-) mice, indicating a biological correlation between CD11b and the inflammatory response in abdominal aortic aneurysm. In vitro, the number of ITGAM(-/-) bone marrow-derived macrophages (BMDMs) that adhered to endothelial cells was significantly lower than the number of wild-type BMDMs. Moreover, the CD11b monoclonal antibody and CD11b agonist leukadherin-1 decreased and increased the number of adherent wild-type BMDMs, respectively. Through RNA sequencing, genes associated with leukocyte transendothelial migration were found to be downregulated in ITGAM(-/-) BMDMs. Furthermore, immunoprecipitation-mass spectrometry analysis predicted that the Akt pathway might be responsible for the impaired transmigratory ability of ITGAM(-/-) BMDMs. The reduced activation of Akt was then confirmed, and the Akt agonist SC79 partially rescued the transendothelial migratory function of ITGAM(-/-) BMDMs. Conclusions CD11b might promote the development and progression of abdominal aortic aneurysm by mediating the endothelial cells adhesion and transendothelial migration of circulating monocytes/macrophages.
| S-EPMC8174368 | biostudies-literature
Project description:Objectives: Exposure to ionizing radiation has been linked to cardiovascular diseases. However, the impact of moderate doses of radiation on abdominal aortic aneurysm (AAA) remains unknown. Approaches : Angiotensin II-infused Apoe-/- mice were irradiated (acute, 1 Gray) either 3 days before (Day-3) or 1 day after (Day+1) pomp implantation. Primary aortic smooth muscle cells (SMCs) isolated were irradiated (acutely 1 Gray) for mechanistic studies and functional tested in vitro. Results: Day-3 and Day+1 irradiation resulted in a significant reduction in aorta dilation (Control: 1.39+/-0.12; Day-3: 1.12+/-0.11; Day+1: 1.15+/-0.08 mm, P<0.001) and AAA incidence (Control: 81.0%; Day-3: 33.3%, Day+1: 53.3%) compared to the non_x0002_irradiated group. Day-3 and Day+1 irradiation led to an increase in collagen content in the adventitia (Thickness control: 23.64+/-2.9; Day-3: 54.39+/-15.5; Day+1 37.55+/- 10.8 mm, P=0.006). However, the underlying protective mechanisms were different between Day-3 and Day+1 groups. Irradiation before Angiotensin II (AngII) infusion mainly modulated vascular smooth muscle cells (VSMCs) phenotype with a decrease in contractile profile and enhanced proliferative and migratory activity. Irradiation after AngII infusion led to an increase in macrophage content with a local anti-inflammatory phenotype characterized by the upregulation of M2-like gene and IL-10 expression. Conclusion: Moderate doses of ionizing radiation mitigates AAA either through VSCM phenotype or inflammation modulation according to the time of irradiation.
2024-10-24 | GSE270106 | GEO
Project description:Oxidative stress plays an important role in the formation of abdominal aortic aneurysm (AAA), and we have recently established a causal role of uncoupled eNOS in this severe human disease. We have also shown that activation of NADPH oxidase (NOX) lies upstream of uncoupled eNOS. Therefore, identification of the specific NOX isoforms that are required for eNOS uncoupling and AAA formation would ultimately lead to novel therapies for AAA. In the present study, we used the Ang II infused hph-1 mice to examine the roles of NOX isoforms in the development of AAA. We generated double mutants of hph-1-NOX1, hph-1-NOX2, hph-1-p47phox, and hph-1-NOX4. After two weeks of Ang II infusion, the incidence rate of AAA substantially dropped from 76.5% in Ang II infused hph-1 mice (n=34) to 11.1%, 15.0%, 9.5% and 0% in hph-1-NOX1 (n=27), hph-1-NOX2 (n=40), hph-1-p47phox (n=21), and hph-1-NOX4 (n=33) double mutant mice, respectively. The size of abdominal aortas of the four double mutant mice, determined by ultrasound analyses, was significantly smaller than the hph-1 mice. Aortic nitric oxide and H4B bioavailabilities were markedly improved in the double mutants, while superoxide production and eNOS uncoupling activity were substantially diminished. These effects seemed attributed to an endothelial specific restoration of dihydrofolate reductase expression and activity, deficiency of which has been shown to induce eNOS uncoupling and AAA formation in both Ang II-infused hph-1 and apoE null animals. In addition, over-expression of human NOX4 N129S or T555S mutant newly identified in aneurysm patients increased hydrogen peroxide production, further implicating a relationship between NOX and human aneurysm. Taken together, these data indicate that NOX isoforms 1, 2 or 4 lies upstream of dihydrofolate reductase deficiency and eNOS uncoupling to induce AAA formation. These findings may promote development of novel therapeutics for the treatment of the disease by inhibiting NOX signaling.
| S-EPMC5133668 | biostudies-literature