Deficiency of IL12p40 (Interleukin 12 p40) Promotes Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysm

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.

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

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00498-3 ◽

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.

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Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm

Physiological Genomics ◽

10.1152/physiolgenomics.00044.2011 ◽

2011 ◽

Vol 43 (17) ◽

pp. 993-1003 ◽

Cited By ~ 42

Author(s):

Joshua M. Spin ◽

Mark Hsu ◽

Junya Azuma ◽

Maureen M. Tedesco ◽

Alicia Deng ◽

...

Keyword(s):

Gene Expression ◽

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Network Analysis ◽

Aortic Aneurysm ◽

Mapk Signaling ◽

Aortic Dilatation ◽

Ang Ii ◽

Abdominal Aortic ◽

Aneurysm Development

We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE−/− model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-β/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non-CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets.

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

Hypertension ◽

10.1161/hyp.62.suppl_1.a47 ◽

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.

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SGLT-2 (Sodium-Glucose Cotransporter 2) Inhibition Reduces Ang II (Angiotensin II)–Induced Dissecting Abdominal Aortic Aneurysm in ApoE (Apolipoprotein E) Knockout Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.312659 ◽

2019 ◽

Vol 39 (8) ◽

pp. 1614-1628 ◽

Cited By ~ 9

Author(s):

Rebeca Ortega ◽

Aida Collado ◽

Francisca Selles ◽

Herminia Gonzalez-Navarro ◽

Maria-Jesus Sanz ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Apolipoprotein E ◽

Knockout Mice ◽

Ang Ii ◽

Sodium Glucose Cotransporter ◽

Abdominal Aortic ◽

Apolipoprotein E Knockout Mice

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PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysm in Mice

Hypertension ◽

10.1161/hypertensionaha.118.11184 ◽

2018 ◽

Vol 72 (5) ◽

pp. 1189-1199 ◽

Cited By ~ 7

Author(s):

Er-shun Liang ◽

Wen-wu Bai ◽

Hao Wang ◽

Jian-ning Zhang ◽

Fan Zhang ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Ang Ii ◽

Abdominal Aortic ◽

Parp 1

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MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.764337 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bartosz Pilecki ◽

Paulo V. S. D. de Carvalho ◽

Katrine L. Kirketerp-Møller ◽

Anders Schlosser ◽

Karin Kejling ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Apolipoprotein E ◽

Macrophage Infiltration ◽

Elastic Membrane ◽

Ang Ii ◽

Monocyte Migration ◽

Age Related ◽

Abdominal Aortic

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.

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

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.676612 ◽

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.

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