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.

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.

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 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 019: Vascular Smooth Muscle ADAM17 Contributes To Angiotensin II-induced Abdominal Aortic Aneurysm Formation But Not Hypertension In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Toshiyuki Tsuji ◽  
Takehiko Takayanagi ◽  
Katherine Elliott ◽  
Takashi Obama ◽  
Kevin Crawford ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Saline Infusion ◽  
Internal Diameter ◽  
Egfr Activation ◽  
Abdominal Aortic

Enhancement of the renin angiotensin II (AngII) system has been implicated in the development of abdominal aortic aneurysm (AAA). However, detailed molecular mechanism(s) by which AngII promotes AAA remain uncertain. We have demonstrated the critical role of a metalloprotease, ADAM17, in AngII-induced EGFR transactivation and subsequent hypertrophy in vascular smooth muscle cells (VSMC). In caveolin 1-/- mice, AAA formation induced by AngII plus beta-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, was attenuated. The attenuation of AAA formation was associated with suppression of ADAM17 induction and EGFR activation. Others have reported that systemic ADAM17 silencing attenuated CaCl2-induced AAA formation in mice. However, the cell type specific mechanism that is mediating the deleterious effect of ADAM17 in AAA is not well understood. Here, we tested our hypothesis that VSMC ADAM17 activation is required for AngII-promoted AAA formation using ADAM17flox/flox mice bred with sm22a Cre mice. 8 week old mice were co-infused with AngII 1000 ng/kg/min (4w) and BAPN 150 mg/kg/day (2w) or control saline (4w), and AAA formation was evaluated by echo (internal diameter) and measurement (external diameter) of the aortae. In control Cre-/- mice with the co-infusion, 52.4% (11/21) were dead due to aortic rupture/dissection. All surviving Cre-/- mice with co-infusion had AAA with max external/internal diameter (mm) of 2.18±0.55/1.75±0.33 vs 1.01±0.22/1.06±0.02 with saline infusion (p<0.01). In contrast, VSMC ADAM17 deficient Cre+/- with co-infusion did not die or develop AAA. The max external/internal diameter (mm) of AA in Cre+/- with co-infusion was 1.03±0.11/1.05±0.05 vs 1.01±0.12/1.27±0.21 with saline infusion. In contrast, both Cre-/- and +/- mice with the co-infusion developed hypertension assessed by telemetry (MAP mmHg: 161±15 vs 154±12). The ADAM17 deletion was also associated with less EGFR activation, ER/oxidative stress and extravascular fibrosis/matrix deposition. In conclusion, VSMC ADAM17 appears to be a critical metalloprotease contributing to AAA formation but not hypertension induced by AngII + BAPN. The mechanism by which VSMC ADAM17 promotes AAA seems to involve activation of EGFR and induction of ER/oxidative stress.

scholarly journals Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase

2014 ◽  
Vol 126 (11) ◽  
pp. 785-800 ◽  
Author(s):  
Takehiko Takayanagi ◽  
Kevin J. Crawford ◽  
Tomonori Kobayashi ◽  
Takashi Obama ◽  
Toshiyuki Tsuji ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Therapeutic Target ◽  
Lysyl Oxidase ◽  
Caveolin 1 ◽  
Abdominal Aortic ◽  
Aneurysm Development ◽  
Novel Therapeutic

Caveolin 1 deficiency protected mice from abdominal aortic aneurysm development induced by angiotensin II, which is probably due to suppression of ADAM17 activation and subsequent oxidative stress. Caveolin 1 may provide a novel therapeutic target for prevention of abdominal aortic aneurysm.

Peri-Adventitial Delivery of Smooth Muscle Cells in Porous Collagen Scaffolds for Treatment of Experimental Abdominal Aortic Aneurysm

2021 ◽  
Author(s):  
Joscha Mulorz ◽  
Mahdis Shayan ◽  
Caroline Hu ◽  
Cynthia Alcazar ◽  
Alex H.P Chan ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vessel Wall ◽  
Muscle Cells ◽  
Collagen Scaffolds ◽  
Abdominal Aortic ◽  
Direct Delivery

Abdominal aortic aneurysm (AAA) is associated with the loss of vascular smooth muscle cells (SMCs) within the vessel wall. Direct delivery of therapeutic cells is challenging due to impaired mechanical...

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