scholarly journals Sildenafil (Viagra) Aggravates the Development of Experimental Abdominal Aortic Aneurysm

2022 ◽  
Author(s):  
Chongyang Zhang ◽  
Amy Mohan ◽  
Hangchuan Shi ◽  
Chen Yan
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Proximity Ligation Assay ◽  
Collagen Formation ◽  
Protein Levels ◽  
Elastin Degradation ◽  
Myosin Light Chain 2 ◽  
Abdominal Aortic ◽  
Dependent Protein ◽  
Phosphodiesterase Type

Background cGMP‐hydrolyzing phosphodiesterase type 5 (PDE5) regulates vascular smooth muscle cell (SMC) contraction by antagonizing cGMP‐dependent protein kinase I (PKGI)–dependent SMC relaxation. SMC contractile dysfunction is implicated in the pathogenesis of aortic aneurysm. PDE5 inhibitors have been used for treating erectile dysfunction, such as drug Viagra (sildenafil). However, a few clinical cases have reported the association of Viagra usage with aortic dissection, and reduced PDE5A expression was found in human aortic aneurysm tissues. Therefore, we aimed to investigate the effect of sildenafil on experimental abdominal aortic aneurysm (AAA), the most common form of aortic aneurysm in elderly men. Methods and Results AAA was induced in C57BL/6J male mice by periaortic elastase in combination with blocking elastin/collagen formation via 3‐aminopropionitrile fumarate salt for 35 days. PDE5A protein levels detected by immunostaining were significantly reduced in mouse AAA. Sildenafil application in drinking water significantly aggravated aortic wall dilation and elastin degradation with pre‐existing moderate AAA. The phosphorylation level of myosin light chain 2 at Ser19, a biochemical marker of SMC contraction, was significantly reduced by sildenafil in AAA. Proximity ligation assay further revealed that the interaction between cGMP and PKGI was significantly increased by sildenafil in AAA, suggesting an elevation of PKGI activation in AAA. Conclusions Sildenafil treatment aggravated the degradation of elastin fibers and progression of experimental AAA by dysregulating cGMP and contractile signaling in SMCs. Our findings may raise the caution of clinical usage of Viagra in aneurysmal patients.

scholarly journals IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Hao Chai ◽  
ZhongHao Tao ◽  
YongChao Qi ◽  
HaoYu Qi ◽  
Wen Chen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Maximal Diameter ◽  
Abdominal Aortic ◽  
Primary Mouse

Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

scholarly journals Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm

2019 ◽  
Vol 133 (13) ◽  
pp. 1421-1438 ◽  
Author(s):  
Miquel Navas-Madroñal ◽  
Cristina Rodriguez ◽  
Modar Kassan ◽  
Joan Fité ◽  
José R. Escudero ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Er Stress ◽  
Mitochondrial Biogenesis ◽  
Atmospheric Pressure Chemical Ionization ◽  
Vascular Wall ◽  
Protein Levels ◽  
Abdominal Aortic ◽  
Healthy Donors

Abstract Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of cardiovascular diseases (CVDs), although their contribution to AAA development is uncertain. Therefore, we aimed to determine their implication in AAA and investigated the profile of oxysterols in plasma, specifically 7-ketocholesterol (7-KC), as an ER stress inducer. In the present study, we determined aortic ER stress activation in a large cohort of AAA patients compared with healthy donors. Higher gene expression of activating transcription factor (ATF) 6 (ATF6), IRE-1, X-binding protein 1 (XBP-1), C/EBP-homologous protein (CHOP), CRELD2 and suppressor/enhancer of Lin-12-like (SEL1L) and greater protein levels of active ATF6, active XBP1 and of the pro-apoptotic protein CHOP were detected in human aneurysmatic samples. This was accompanied by an exacerbated apoptosis, higher reactive oxygen species (ROS) production and by a reduction in mitochondrial biogenesis in the vascular wall of AAA. The quantification of oxysterols, performed by liquid chromatography-(atmospheric pressure chemical ionization (APCI))-mass spectrometry, showed that levels of 7-KC were significantly higher while those of 7α-hydroxycholesterol (HC), 24-HC and 27-HC were lower in AAA patients compared with healthy donors. Interestingly, the levels of 7-KC correlate with the expression of ER stress markers. Our results evidence an induction of ER stress in the vascular wall of AAA patients associated with an increase in circulating 7-KC levels and a reduction in mitochondrial biogenesis suggesting their implication in the pathophysiology of this disease.

Abstract 102: Model-Dependent Influence of Prior Splenectomy on Experimental Abdominal Aortic Aneurysm Progression

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Baohui Xu ◽  
Yasunori Iida ◽  
Xiaolei Hu ◽  
Richard Yuan ◽  
Haojun Xuan ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Initial Step ◽  
Aortic Diameter ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Abdominal Aortic

Objective: Abdominal aortic aneurysm (AAA) is a macrophage-driven, inflammatory vascular disease. Thus, mobilization of macrophage precursors from the bone marrow and/or splenic reservoir may represent a crucial initial step for AAA formation. Prior evidence suggests that splenic monocytes are important initial contributors to ischemic myocardial injury, their role in AAA pathogenesis remains unknown. We surgically removed the spleen prior to AAA creation to evaluate the influence of splenic monocytes on aneurysm pathophysiology. Methods: AAAs were created in either 1) male C57BL/6 mice by infrarenal intra-aortic porcine pancreatic elastase (PPE) infusion or 2) male ApoE deficient mice by continuous subdermal angiotensin II infusion (ApoE KO/Ang II model). Splenectomy was performed immediately prior to AAA creation in both models. Aortic diameter was serially monitored via ultrasonography, and aortae harvested at sacrifice for histopathology. Results: In sham splenectomy mice, PPE infusion led to significant aortic enlargement. AAA (≥50% aortic diameter increase) developed in all sham/PPE mice within 14 days (n=10). Splenectomy effectively eliminated PPE-induced aortic enlargement, with preservation of medial elastin and smooth muscle cell density and minimal inflammation compared to sham. In contrast, Ang II infusion in ApoE deficient produced similar-sized or larger AAA in splenectomized mice compared to sham, with elastin degradation, smooth muscle cell depletion undistinguishable between the groups. Conclusion: Splenectomy confers differential protection from AAA in mice, depending on the model/method employed for aneurysm formation. While this experiment underscores important limitations to mouse-based AAA modeling, the splenic monocyte reservoir may represent an important driver of AAA pathophysiology.

scholarly journals Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model

2012 ◽  
Vol 302 (7) ◽  
pp. H1378-H1386 ◽  
Author(s):  
Paul D. DiMusto ◽  
Guanyi Lu ◽  
Abhijit Ghosh ◽  
Karen J. Roelofs ◽  
Gang Su ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Serine Proteases ◽  
Protective Factor ◽  
Experimental Aneurysm ◽  
Male And Female ◽  
Protein Levels ◽  
Aneurysm Formation ◽  
Abdominal Aortic ◽  
Pai 1

The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1−/−mice 8–12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% ( P < 0.001). PAI-1−/−males increased 204% and females 161%, significantly more than their WT counterparts ( P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males ( P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1−/−males and females compared with their WT counterparts. PAI-1−/−females had significantly higher serum plasmin levels compared with WT females ( P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1−/−animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.

scholarly journals Inhibition of Peptidyl Arginine Deiminase 4-Dependent Neutrophil Extracellular Trap Formation Reduces Angiotensin II-Induced Abdominal Aortic Aneurysm Rupture in Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Ming Wei ◽  
Xia Wang ◽  
Yanting Song ◽  
Di Zhu ◽  
Dan Qi ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Tissue Injury ◽  
Arginine Deiminase ◽  
Tunel Staining ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Abdominal Aortic

Objective: Neutrophil infiltration plays an important role in the initiation and development of abdominal aortic aneurysm (AAA). Recent studies suggested that neutrophils could release neutrophil extracellular traps (NETs), leading to tissue injury in cardiovascular diseases. However, the role of NETs in AAA is elusive. This study aimed to investigate the role and underlying mechanism of NETs in AAA development.Methods and Results: An angiotensin II (Ang II) infusion-induced AAA model was established to investigate the role of NETs during AAA development. Immunofluorescence staining showed that citrullinated histone 3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) (NET marker) expressions were significantly increased in Ang II-infused ApoE−/− mice. The circulating double-stranded DNA (dsDNA) level was also elevated, indicating the increased NET formation during AAA. PAD4 inhibitor YW3-56 inhibited Ang II-induced NET formation. Disruption of NET formation by YW3-56 markedly reduced Ang II-induced AAA rupture, as revealed by decreased aortic diameter, vascular smooth muscle cell (VSMC) apoptosis, and elastin degradation. Apoptosis of VSMC was evaluated by TUNEL staining and Annexin V-FITC/PI staining through flow cytometry. Western blot and inhibition experiments revealed that NETs induced VSMC apoptosis via p38/JNK pathway, indicating that PAD4-dependent NET formation played an important role in AAA.Conclusions: This study suggests that PAD4-dependent NET formation is critical for AAA rupture, which provides a novel potential therapeutic strategy for AAA disease.

Abstract 9911: Hypoxia-inducible Factor-1α Knockout in Myeloid Lineage exaggerates Angiotensin II-induced Abdominal Aortic Aneurysm

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yusuke Takahara ◽  
Tomotake Tokunou ◽  
Hiroshi Kojima ◽  
Toshihiro Ichiki ◽  
Yoshitaka Hirooka ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Protective Effect ◽  
Hypoxia Inducible Factor ◽  
Myeloid Lineage ◽  
Knock Out ◽  
Elastin Degradation ◽  
Abdominal Aortic ◽  
Knock Out Mice

Background: Hypoxia-inducible factor-1α (Hif1α) is a transcriptional factor that regulates various genes reacting hypoxic conditions. In atherosclerotic legion, Hif1α is thought to be regulating inflammatory responses. We previously reported that myeloid specific Proryl hydroxylase domain protein2 deletion had protective effect on cardiovascular disease in animal model. The roll of Hif1α of myeloid lineage in inflammatory response is not determined. Methods and Results: Myeloid specific Hif1α knock out mice (MyHif KO) were created using Cre-lox recombination. MyHif KO mice were crossed with Apolipoprotein E knockout (ApoEKO) mice to create double knock out mice (MyHif/ApoE DKO group, n=18). ApoEKO with Hif1α flox/flox (without Cre recombinase) mice were used as control group (n=11). Two groups were fed with high fat diet (HFD) and infused with Angiotensin II (AII, 1800ng/kg/min) by osmotic mini pump for 4 weeks to promote abdominal aortic aneurysm (AAA) formation. The genotype of mice was blinded during experiment. There was no significant difference in survival rate between two groups. MyHif/ApoE DKO increased AAA formation rate (94.4% vs 81.8% in control) and aortic diameter (2.42mm±0.21mm vs 1.89±0.27mm in control). AAA classification reported by Daugherty et al was significantly exaggerated in MyHif/ApoE DKO group (2.75±0.35 vs 1.63±0.46 in control, P=0.03). Elastin degradation grade was checked by Elastica van Gieson staining. MyHif/ApoE DKO also deteriorated the elastin degradation grade (3.91±0.08 vs 3.25±0.31, P=0.01). The number of macrophages which migrated to abdominal aorta was increased in MyHif/ApoE DKO group (565±110.3/section vs 260.5±136.5/section in control, P=0.0507), whereas MyHif/ApoE DKO did not change the glucose level, blood pressure and body weight. Peritoneal macrophages from MyHif/ApoE DKO were significantly activated the migration induced by monocyte chemotactic protein-1 in dose dependent manner. Conclusion: Hif1α of myeloid lineage might have vascular protective effect via suppressing the macrophage activation in the model of AII-induced AAA in mice.

A Thick-Walled Fluid–Solid-Growth Model of Abdominal Aortic Aneurysm Evolution: Application to a Patient-Specific Geometry

2015 ◽  
Vol 137 (3) ◽  
Author(s):  
Andrii Grytsan ◽  
Paul N. Watton ◽  
Gerhard A. Holzapfel
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Disease ◽  
Arterial Wall ◽  
Cylindrical Tube ◽  
Patient Specific ◽  
Constant Density ◽  
Disease Evolution ◽  
Elastin Degradation ◽  
Abdominal Aortic

We propose a novel thick-walled fluid–solid-growth (FSG) computational framework for modeling vascular disease evolution. The arterial wall is modeled as a thick-walled nonlinearly elastic cylindrical tube consisting of two layers corresponding to the media-intima and adventitia, where each layer is treated as a fiber-reinforced material with the fibers corresponding to the collagenous component. Blood is modeled as a Newtonian fluid with constant density and viscosity; no slip and no-flux conditions are applied at the arterial wall. Disease progression is simulated by growth and remodeling (G&R) of the load bearing constituents of the wall. Adaptions of the natural reference configurations and mass densities of constituents are driven by deviations of mechanical stimuli from homeostatic levels. We apply the novel framework to model abdominal aortic aneurysm (AAA) evolution. Elastin degradation is initially prescribed to create a perturbation to the geometry which results in a local decrease in wall shear stress (WSS). Subsequent degradation of elastin is driven by low WSS and an aneurysm evolves as the elastin degrades and the collagen adapts. The influence of transmural G&R of constituents on the aneurysm development is analyzed. We observe that elastin and collagen strains evolve to be transmurally heterogeneous and this may facilitate the development of tortuosity. This multiphysics framework provides the basis for exploring the influence of transmural metabolic activity on the progression of vascular disease.

Sign in / Sign up

Export Citation Format

Share Document