scholarly journals Targeting Tyrosine Hydroxylase for Abdominal Aortic Aneurysm: Impact on Inflammation, Oxidative Stress, and Vascular Remodeling

Hypertension ◽  
2021 ◽  
Author(s):  
Laia Cañes ◽  
Judith Alonso ◽  
Carme Ballester-Servera ◽  
Saray Varona ◽  
José R. Escudero ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Tyrosine Hydroxylase ◽  
Aortic Aneurysm ◽  
Specific Inhibitor ◽  
Orphan Receptor ◽  
Matrix Metalloproteinase 2 ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
The Impact

Pharmacological treatments for preventing abdominal aortic aneurysm (AAA) rupture or slowing aneurysm progression remain a challenge. It is increasingly recognized that sympathetic activity might play a role in the pathogenesis of AAA; however, the impact of this pathway remains unclear. Here, we show that the expression of tyrosine hydroxylase ( TH ), dopamine β-hydroxylase ( DBH ), and the norepinephrine transporter SLC6A2 is upregulated in abdominal aorta samples from AAA patients and in the aneurysmal aorta from 2 animal models susceptible to Ang II (angiotensin II)–induced AAA: the apolipoprotein E-deficient (ApoE −/− ) model and a transgenic mouse that overexpresses the human nuclear receptor NOR-1 (neuron-derived orphan receptor-1) in the vascular wall (TgNOR-1 VSMC ). TH localizes to sympathetic nerves innervating the local vasculature, but also to inflammatory cells, and scattered vascular smooth muscle cell in human and mouse AAA. Interestingly, the preventive effect of doxycycline on AAA formation in Ang II–treated TgNOR-1 VSMC mice was associated to the normalization of vascular Th expression. Moreover, the TH specific inhibitor α-methyl- p -tyrosine protected against Ang II–induced AAA formation, limiting the progressive increase in aortic diameter without affecting blood pressure. The drug normalized MMP2 (matrix metalloproteinase 2) expression and MMP activity, preserving elastin integrity, attenuated the Ang II–mediated rise in vascular oxidative stress and inflammatory markers and reduced the inflammatory infiltrate. Finally, NOR-1, whose expression correlated with that of TH in human AAA, was able to drive human TH transcriptional activity in transient transfection assays. Therefore, the upregulation of the TH pathway could be critical in the pathophysiology of AAA, supporting the potential of pharmacological strategies targeting TH for AAA management.

scholarly journals Deficiency of peroxiredoxin 2 exacerbates angiotensin II-induced abdominal aortic aneurysm

2020 ◽  
Vol 52 (9) ◽  
pp. 1587-1601
Author(s):  
Se-Jin Jeong ◽  
Min Ji Cho ◽  
Na Young Ko ◽  
Sinai Kim ◽  
In-Hyuk Jung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Negative Regulator ◽  
Aortic Dilatation ◽  
Ang Ii ◽  
Peroxiredoxin 2 ◽  
Structural Deterioration ◽  
Abdominal Aortic

Abstract Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease characterized by structural deterioration of the aorta caused by inflammation and oxidative stress, leading to aortic dilatation and rupture. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, has been reported as a potential negative regulator of inflammatory vascular diseases, and it has been identified as a protein that is increased in patients with ruptured AAA compared to patients with nonruptured AAA. In this study, we demonstrated that PRDX2 was a pivotal factor involved in the inhibition of AAA progression. PRDX2 levels were increased in AAA compared with those in normal aortas in both humans and mice. Ultrasound imaging revealed that the loss of PRDX2 accelerated the development of AAA in the early stages and increased AAA incidence in mice infused with angiotensin II (Ang II). Prdx2−/− mice infused with Ang II exhibited increased aortic dilatation and maximal aortic diameter without a change in blood pressure. Structural deterioration of the aortas from Prdx2−/− mice infused with Ang II was associated with increases in the degradation of elastin, oxidative stress, and intramural thrombi caused by microhemorrhages, immature neovessels, and the activation of matrix metalloproteinases compared to that observed in controls. Moreover, an increase in inflammatory responses, including the production of cell adhesion molecules and the accumulation of inflammatory cells and proinflammatory cytokines due to PRDX2 deficiency, accelerated Ang II-induced AAA progression. Our data confirm that PRDX2 plays a role as a negative regulator of the pathological process of AAA and suggest that increasing PRDX2 activity may be a novel strategy for the prevention and treatment of AAA.

Abstract 47: Caveolin-1 is Critical for Abdominal Aortic Aneurysm Induced by Angiotensin II

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Takashi Obama ◽  
Takehiko Takayanagi ◽  
Kevin J Crawford ◽  
Tomonori Kobayashi ◽  
Victor Rizzo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle Cells ◽  
Critical Role ◽  
Ang Ii ◽  
Caveolin 1 ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. Accumulating evidence suggests a role of angiotensin II (Ang II) in abdominal aortic aneurysm (AAA) formation. However, the Ang II-sensitive proximal signaling events primarily responsible for AAA formation remain unclear. We recently reported that caveolin-1 (Cav1) enriched membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation, which is linked to vascular remodeling induced by Ang II. Given that ADAM17 expression is one of the key features in AAA, we have tested our hypothesis that Cav1, a major structural protein of caveolae, plays a critical role for development of AAA by Ang II via regulation of ADAM17. 8 week old male Cav1-/- and the control C57Bl/6 wild-type mice (WT) were co-infused with Ang II (1 μg/kg/min) and β-aminopropionitrile (BAPN: 150mg/kg/day) for 4 weeks to induce AAA. In WT with the co-infusion, 58% (14/24) were dead due to aortic rupture/dissection. All surviving WT with co-infusion had AAA with max diameter (mm) of 2.6±0.18 vs 0.93±0.09 with saline infusion (p<0.01). In contrast, we found that Cav1-/- with co-infusion did not die or develop AAA. The max diameter (mm) of AAA in Cav1-/- with co-infusion was 1.0±0.04 vs 1.1±0.06 with saline infusion (n=7). In contrast, both WT and Cav1-/- with the co-infusion developed hypertension assessed by telemetry (MAP mmHg: 151±5 vs 161±7). We found an increased expression of ADAM17 by IHC and qPCR, and enhanced phosphorylation of EGFR by IHC in WT abdominal aortae with aneurysms. These events were markedly attenuated in Cav1-/- aorta with co-infusion (ADAM17/18S mRNAx10,000 = 3.08±0.71 vs 0.97±0.42 p<0.05, n=4). Furthermore, Cav1-/- aortae showed less ER and oxidative stress compared to WT aortae assessed by IHC. In addition, Cav1 silencing induced by adenovirus encoding Cav1 targeting siRNA embedded miRNA in cultured vascular smooth muscle cells prevented Ang II-induced ADAM17 induction and activation. In conclusion, Cav1 and presumably vascular caveolae microdomains appear to play a critical role in the formation of AAA by Ang II via regulation of the ADAM17/EGFR signaling and subsequent ER/oxidative stress.

scholarly journals Circular RNA RBM33 contributes to extracellular matrix degradation via miR-4268/EPHB2 axis in abdominal aortic aneurysm

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12232
Author(s):  
Shizhi Wang ◽  
Qingwen Yuan ◽  
Wenpeng Zhao ◽  
Weimin Zhou
Keyword(s):  
Extracellular Matrix ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Matrix Metalloproteinase 2 ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Gene Assay ◽  
Ecm Degradation

Background Abdominal aortic aneurysm (AAA) is a complex vascular disease involving expansion of the abdominal aorta. Extracellular matrix (ECM) degradation is crucial to AAA pathogenesis, however, the specific molecular mechanism remains unclear. This study aimed to investigate differentially expressed circular RNAs (DEcircRNAs) involved in ECM degradation of AAA. Methods Transcriptome sequencing was used to analyze the DEcircRNAs between the AAA tissues and normal tissues. The expression of circRNAs in tissues and cells was validated using quantitative reverse transcription PCR (RT-qPCR). Overexpression of circRNAs in vascular smooth muscle cells (VSMCs) treated with angiotensin II (Ang II) was employed to explore its effect on ECM degradation of AAA. Bioinformatic technology, luciferase reporter gene assay, RT-qPCR, and rescue experiment were employed to evaluate the regulatory mechanism of circRNA. Results We identified 65 DEcircRNAs in AAA tissues compared with normal abdominal aortic tissues, including 30 up-regulated and 35 down-regulated circRNAs, which were mainly involved in inflammation and ECM-related functions and pathways. Moreover, circRBM33 was significantly increased in AAA tissues and Ang II-induced VSMCs compared with control samples. Overexpression of circRBM33 increased the expression of ECM-related molecule matrix metalloproteinase-2 and reduced the tissue inhibitor of matrix metalloproteinases-1 expression. Mechanistically, miR-4268 targeted binding to circRBM33 and inhibited the luciferase activity of circRBM33. Overexpression of circRBM33 induced the expression of EPH receptor B2 (EPHB2), and this effect was countered by miR-4268 mimics. Conclusions Overall, our data suggest that circRBM33 might be involved in AAA progression by regulating ECM degradation via the miR-4268/EPHB2 axis.

scholarly journals Role of myeloperoxidase in abdominal aortic aneurysm formation: mitigation by taurine

2017 ◽  
Vol 313 (6) ◽  
pp. H1168-H1179 ◽  
Author(s):  
Ha Won Kim ◽  
Andra L. Blomkalns ◽  
Mourad Ogbi ◽  
Manesh Thomas ◽  
Daniel Gavrila ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Gene Deletion ◽  
Hypochlorous Acid ◽  
Attractive Potential ◽  
Ang Ii ◽  
Amyloid A ◽  
Abdominal Aortic

Oxidative stress plays a fundamental role in abdominal aortic aneurysm (AAA) formation. Activated polymorphonuclear leukocytes (or neutrophils) are associated with AAA and express myeloperoxidase (MPO), which promotes inflammation, matrix degradation, and other pathological features of AAA, including enhanced oxidative stress through generation of reactive oxygen species. Both plasma and aortic MPO levels are elevated in patients with AAA, but the role of MPO in AAA pathogenesis has, heretofore, never been investigated. Here, we show that MPO gene deletion attenuates AAA formation in two animal models: ANG II infusion in apolipoprotein E-deficient mice and elastase perfusion in C57BL/6 mice. Oral administration of taurine [1% or 4% (wt/vol) in drinking water], an amino acid known to react rapidly with MPO-generated oxidants like hypochlorous acid, also prevented AAA formation in the ANG II and elastase models as well as the CaCl2 application model of AAA formation while reducing aortic peroxidase activity and aortic protein-bound dityrosine levels, an oxidative cross link formed by MPO. Both MPO gene deletion and taurine supplementation blunted aortic macrophage accumulation, elastin fragmentation, and matrix metalloproteinase activation, key features of AAA pathogenesis. Moreover, MPO gene deletion and taurine administration significantly attenuated the induction of serum amyloid A, which promotes ANG II-induced AAAs. These data implicate MPO in AAA pathogenesis and suggest that studies exploring whether taurine can serve as a potential therapeutic for the prevention or treatment of AAA in patients merit consideration. NEW & NOTEWORTHY Neutrophils are abundant in abdominal aortic aneurysm (AAA), and myeloperoxidase (MPO), prominently expressed in neutrophils, is associated with AAA in humans. This study demonstrates that MPO gene deletion or supplementation with the natural product taurine, which can scavenge MPO-generated oxidants, can prevent AAA formation, suggesting an attractive potential therapeutic strategy for AAA.

Stereoscopically Observed Deformations of a Compliant Abdominal Aortic Aneurysm Model

2011 ◽  
Vol 133 (11) ◽  
Author(s):  
Clark A. Meyer ◽  
Eric Bertrand ◽  
Olivier Boiron ◽  
Valérie Deplano
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Computational Models ◽  
Imaging System ◽  
Strain Differences ◽  
Cyclic Strain ◽  
Experimental Models ◽  
Body Motion ◽  
Abdominal Aortic ◽  
The Impact

A new experimental setup has been implemented to precisely measure the deformations of an entire model abdominal aortic aneurysm (AAA). This setup addresses a gap between the computational and experimental models of AAA that have aimed at improving the limited understanding of aneurysm development and rupture. The experimental validation of the deformations from computational approaches has been limited by a lack of consideration of the large and varied deformations that AAAs undergo in response to physiologic flow and pressure. To address the issue of experimentally validating these calculated deformations, a stereoscopic imaging system utilizing two cameras was constructed to measure model aneurysm displacement in response to pressurization. The three model shapes, consisting of a healthy aorta, an AAA with bifurcation, and an AAA without bifurcation, were also evaluated with computational solid mechanical modeling using finite elements to assess the impact of differences between material properties and for comparison against the experimental inflations. The device demonstrated adequate accuracy (surface points were located to within 0.07 mm) for capturing local variation while allowing the full length of the aneurysm sac to be observed at once. The experimental model AAA demonstrated realistic aneurysm behavior by having cyclic strains consistent with reported clinical observations between pressures 80 and 120 mm Hg. These strains are 1–2%, and the local spatial variations in experimental strain were less than predicted by the computational models. The three different models demonstrated that the asymmetric bifurcation creates displacement differences but not cyclic strain differences within the aneurysm sac. The technique and device captured regional variations of strain that are unobservable with diameter measures alone. It also allowed the calculation of local strain and removed rigid body motion effects on the strain calculation. The results of the computations show that an asymmetric aortic bifurcation created displacement differences but not cyclic strain differences within the aneurysm sac.

Redox proteomic analysis of serum from aortic anerurysm patients: insights on oxidation of specific protein target

2016 ◽  
Vol 12 (7) ◽  
pp. 2168-2177 ◽  
Author(s):  
Cristiano Spadaccio ◽  
Raffaella Coccia ◽  
Marzia Perluigi ◽  
Gilda Pupo ◽  
Maria Eugenia Schininà ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Proteomic Analysis ◽  
Specific Protein ◽  
Protein Target ◽  
Abdominal Aortic

Oxidative stress is undoubtedly one of the main players in abdominal aortic aneurysm (AAA) pathophysiology.

Abstract 279: Role of Caveolin-1 in Abdominal Aortic Aneurysm induced by Angiotensin II

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Takehiko Takayanagi ◽  
Kevin Crawford ◽  
Tomonori Kobayashi ◽  
Victor Rizzo ◽  
Satoru Eguchi
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Egf Receptor ◽  
Critical Role ◽  
Membrane Microdomains ◽  
Structural Protein ◽  
Caveolin 1 ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. Accumulating evidence suggests that activation of the AT1 receptor by angiotensin II (AngII) in AAA formation. While several downstream signals and target proteins have been identified in this pathway, there is a huge void in our knowledge regarding the AngII-sensitive proximal events primarily responsible for AAA formation. We recently reported that caveolae membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation which linked to vascular remodeling induced by AngII. Given that ADAM17 expression is one of the key features in AAA, we have tested our hypothesis that caveolin-1 (Cav1), a major structural protein of caveolae, in the vasculature plays a critical role for development of AAA via its regulation on ADAM17. 8 week old male Cav1-/- mice and the control C57Bl/6 wild-type (WT) mice were co-infused with AngII and BAPN, a lysyl oxidase inhibitor, to induce AAA. We found that Cav1-/- mice did not develop AAA compared to C57Bl/6 mice in spite of hypertension assessed by telemetry in both groups. This finding suggests that the AngII signaling essential for vascular contraction remains in place in Cav1-/- mice. We found an increased expression of ADAM17 and auto-phosphorylation of EGFR in WT abdominal aortae with aneurysms that were markedly attenuated in Cav1-/- mice infused with AngII+BAPN. Furthermore, Cav1-/- mice with the infusion showed less oxidative stress and ER stress than their WT counterparts as assessed by nitrotyrosine staining and KDEL/p-eIF2a staining, respectively. In conclusion, Cav1 and presumably vascular caveolae micro-domain appear to play a critical role in the formation of AAA in mice via regulation of the ADAM17/EGFR signaling axis and subsequent induction of ER/oxidative stress.

Abstract 598: Deletion of Microsomal PGE Synthase-1 Decreases Oxidative Stress and Protects Against Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Miao Wang ◽  
Jane Stubbe ◽  
Eric Lee ◽  
Wenliang Song ◽  
Emanuela Ricciotti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Density Lipoprotein Receptor ◽  
The Impact

Microsomal (m) prostaglandin (PG) E 2 synthase(S)-1, an enzyme that catalyzes the isomerization of the cyclooxygenase (COX) product, PGH 2 , into PGE 2 , is a major source of PGE 2 in vivo . mPGES-1 deletion in mice was found to modulate experimentally evoked pain and inflammation and atherogenesis is retarded in mPGES-1 knockout (KO) mice. The impact of mPGES-1 deletion on formation of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) was studied in mice lacking the low density lipoprotein receptor (LDLR −/− ). AngII infusion increased aortic macrophage recruitment and nitrotyrosine staining while upregulating both mPGES-1 and COX-2 and urinary excretion of the major metabolite of PGE 2 (PGE-M). Deletion of mPGES-1 decreased both the incidence and severity of AAA and depressed excretion of both PGE-M and 8, 12-iso-iPF 2a -VI, which reflects lipid peroxidation in vivo . While Ang II infusion augmented prostaglandin biosynthesis, deletion of mPGES-1 resulted in rediversion to PGD 2 , reflected by its major urinary metabolite. However, deletion of the PGD 2 receptor, DP1, did not affect AAA in Ang II infused LDLR −/− mice. These observations indicate that deletion of mPGES-1 protects against AAA formation by AngII in hyperlipidemic mice, perhaps by decreasing oxidative stress. Inhibition of mPGES-1 may represent an effective treatment to limit aneurysm occurrence and expansion.

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