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

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a279 ◽

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.

Download Full-text

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3602824 ◽

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.

Download Full-text

Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1900152116 ◽

2019 ◽

Vol 116 (26) ◽

pp. 13006-13015 ◽

Cited By ~ 13

Author(s):

Wang Wang ◽

Mengcheng Shen ◽

Conrad Fischer ◽

Ratnadeep Basu ◽

Saugata Hazra ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Aortic Rupture ◽

Critical Role ◽

Neutral Endopeptidase ◽

Negative Regulator ◽

Ang Ii ◽

Direct Role ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress inApln−/yaorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater inApln−/ymice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture inApln−/ymice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) inLdlr−/−mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

Download Full-text

1436Overexpression of Cytotoxic T-Lymphocyte Associated Antigen-4 suppresses aortic immunoinflammatory responses and prevents angiotensin II-induced abdominal aortic aneurysm formation in mice

European Heart Journal ◽

10.1093/eurheartj/ehz748.0071 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

H Amin ◽

N Sasaki ◽

T Yamashita ◽

T Mizoguchi ◽

T Hayashi ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

T Cell ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Immune Responses ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Negative Regulator ◽

Lymphoid Tissues ◽

Abdominal Aortic

Abstract Aims Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. In the present study, we determined the effects of CTLA-4 overexpression on experimental AAA. Methods and results We continuously infused 12-week-old CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E–deficient (Apoe−/−) mice (n=35) or control Apoe−/− mice (n=40) fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter (18%) of AAA (incidence: P=0.0104; mortality: P=0.031; diameter: P=0.011). These protective effects were associated with a decreased number of effector CD4+ T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c+ dendritic cells in lymphoid tissues. In addition, by performing in situ zymography of the abdominal aortic aneurysm lesions, we observed a trend toward a decrease in MMP activity in the aneurysmal lesion following overexpression of CTLA-4. Finally, CTLA-4-Tg/Apoe−/− mice had reduced macrophage and CD4+ T cell accumulation and MMP activity in the aneurysmal lesion, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Conclusion Our findings suggest that CTLA-4 protects against AAA by suppressing immunoinflammatory responses and could be an attractive therapeutic target for AAA.

Download Full-text

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

Hypertension ◽

10.1161/hyp.64.suppl_1.019 ◽

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.

Download Full-text

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.118.311969 ◽

2019 ◽

Vol 39 (2) ◽

pp. 212-223 ◽

Cited By ~ 12

Author(s):

Neekun Sharma ◽

Rishabh Dev ◽

Anthony M. Belenchia ◽

Annayya R. Aroor ◽

Adam Whaley-Connell ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Interleukin 12 ◽

Ang Ii ◽

Abdominal Aortic

Download Full-text

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

Hypertension ◽

10.1161/hypertensionaha.121.17517 ◽

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.

Download Full-text

Abstract 56: Endothelial Adam17 Contributes to Angiotensin Ii-induced Abdominal Aortic Aneurysm in Mice

Hypertension ◽

10.1161/hyp.60.suppl_1.a56 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Tomonori Kobayashi ◽

Takehiko Takayanagi ◽

Tomoki Hashimoto ◽

Carl P Blobel ◽

Satoru Eguchi

Keyword(s):

Oxidative Stress ◽

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Weight Ratio ◽

Oxidase Inhibitor ◽

Heart Weight ◽

Similar Degree ◽

Matrix Deposition ◽

Abdominal Aortic

Enhancement of the renin angiotensin II (AngII) system has been implicated in the development of abdominal aortic aneurysm (AAA) in animal models as well as in clinical studies. However, detailed molecular mechanism(s) by which AngII promotes AAA remain uncertain. We have demonstrated the critical roles of a metalloprotease, ADAM17, in AngII signal transduction in cultured vascular cells. Endothelial AT1 receptor has been recently implicated in oxidative stress. Interestingly, others have reported that ADAM17 expression was enhanced in CaCl2-induced AAA in mice and that systemic ADAM17 silencing attenuated AAA formation. However, the cell type that is mediating the deleterious effect of ADMA17 signaling is not well understood. Here we tested our hypothesis that endothelial ADAM17 activation is required for AngII-promoted AAA formation using ADAM17flox/flox mice bred with Tie2 Cre transgenic mice. 8 week old mice were co-infused with AngII 1000 ng/kg/min (4 weeks) and beta-aminopropionitrile, a lysyl oxidase inhibitor, 150 mg/kg/day (2weeks) or control saline (4 weeks) via osmotic mini-pump, and AAA formation was evaluated by the diameters. AAA formation was attenuated in ADAM17flox/flox Tie2 Cre(+/-) mice compared with ADAM17flox/flox Tie2 Cre(-/-) mice (1.50±0.44 mm vs 3.96±0.61 mm). Cardiac hypertrophy evaluated by heart weight body weight ratio was also attenuated in the Tie2 Cre(+/-) mice (0.0063±0.0005 vs 0.0092±0.0013). However, AngII induced hypertension to a similar degree in both mice groups, as assessed by telemetries. The ADAM17 deletion was associated with less oxidative stress as assessed by anti-nitrotyrosine IHC and less extravascular fibrosis/matrix deposition. Also, the aorta was less stained with MMP2 antibody and phospho-JNK antibody. In conclusion, endothelial ADAM17 appears to be a critical metalloprotease contributing to AAA formation and cardiac remodeling but not hypertension induced by AngII. The mechanism by which endothelial ADAM17 promotes AAA seems to involve induction of oxidative stress, JNK activation and subsequent MMP2 induction.

Download Full-text