Abstract 106: Prevention of Abdominal Aortic Aneurysm by Anti-MiRNA-712 or Anti-miR-205 in Angiotensin II--Infused Mice

Abdominal aortic aneurysm (AAA) is characterized by weakening of the vessel wall, followed by progressive expansion of the diseased aortic segment. MicroRNAs (miRNAs) have emerged as key regulator of gene expression in the cardiovascular diseases and may play a key role in therapeutically targeting AAA development. Although,vascular wall degradation by matrix metalloproteases (MMPs) is the key mechanism in AAA development, their targeting through miRNAs have never been studied. We identified microRNA-712 (miR-712) as a novel Angiotensin II(AngII)-sensitive miRNA which is upregulated in the abdominal aortic endothelium of AngII-infused mice. Mechanistically, we identified that miR-712 directly regulates two key endogenous inhibitors of MMP: tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion inducing cysteine-rich protein with kazal motifs (RECK). Furthermore, inhibition of miR-712 by subcutaneous injection of anti-miR-712 significantly decreased MMP activity in the AngII-infused abdominal aorta wall, prevented the dilatation of aortae and significantly reduced AAA incidence from 80% (8/10) to 20% (2/10), compared to its mismatched control in ApoE -/- mice. Interestingly, based on the seeding sequence, we identified miR-205 as the human homolog of miR-712. miR-205 was also upregulated by AngII treatment and like miR-712 regulated MMPs activity via TIMP3 and RECK. Moreover, inhibition of miR-205 dramatically inhibits AngII-induced AAA development. We also found that miR-205 was significantly upregulated in the aortic sections of AAA patients in comparison to the healthy controls. Our findings demonstrate that AngII-sensitive miRNAs, miR-712 and miR-205, regulate MMP activity through TIMP3 and RECK and play important role in the pathogenesis of AAA. These results suggest that targeting these miRNAs using their inhibitors may hold promise as a therapeutic strategy to prevent the development of AAA.

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148 Loss of TIMP3 leads to adverse remodeling of the vascular wall structure and development of Abdominal Aortic Aneurysm following angiotensin II treatment

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2011.07.105 ◽

2011 ◽

Vol 27 (5) ◽

pp. S115-S116

Author(s):

R. Basu ◽

J. Morton ◽

V. Kandalam ◽

X. Wang ◽

S.T. Davidge ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Vascular Wall ◽

Wall Structure ◽

Abdominal Aortic ◽

Adverse Remodeling

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Ginsenoside Rb1 attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of the JNK and p38 signaling pathways

Vascular Pharmacology ◽

10.1016/j.vph.2015.04.003 ◽

2015 ◽

Vol 73 ◽

pp. 86-95 ◽

Cited By ~ 27

Author(s):

Xiao-Jing Zhang ◽

Chengwei He ◽

Ke Tian ◽

Peng Li ◽

Huanxing Su ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Signaling Pathways ◽

Ginsenoside Rb1 ◽

Abdominal Aortic

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Rapamycin Treatment Attenuates Angiotensin II -induced Abdominal Aortic Aneurysm Formation via VSMC Phenotypic Modulation and Down-regulation of ERK1/2 Activity

Current Medical Science ◽

10.1007/s11596-018-1851-z ◽

2018 ◽

Vol 38 (1) ◽

pp. 93-100 ◽

Cited By ~ 6

Author(s):

Fei-fei Li ◽

Xiao-ke Shang ◽

Xin-ling Du ◽

Shu Chen

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Phenotypic Modulation ◽

Down Regulation ◽

Rapamycin Treatment ◽

Aneurysm Formation ◽

Abdominal Aortic

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Abstract 3718: MMP-12 Inhibitor Reduces Severity of ANGII-induced Aortic Abdominal Aneurysms in apoE−/− Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_473-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Dawn A Savio ◽

Anita R Halpern ◽

Yuchuan Wu ◽

Wei Li ◽

Joseph Sypek ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Vascular Wall ◽

Inflammatory Disorder ◽

Gene Markers ◽

Genetic Ablation ◽

Macrophage Recruitment ◽

Aneurysm Formation ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by local connective tissue degradation, macrophage recruitment and infiltration leading to aortic dilation and rupture. Aneurysms of the abdominal aorta represent a significant cardiovascular risk for which inflammation plays an integral role in the defined pathology. Genetic ablation of metalloprotease-12 (MMP-12) eliminates metalloelastase activity and attenuates aneurysm formation in apoE−/− mice. In the current study, a selective MMP-12 inhibitor, WAY-644 was evaluated in the well-established murine model of ANGII-induced aneurysm formation. This inhibitor displays activity for murine MMP-12, IC50 = 6.3 nM by FRET analysis, with low crossreactivity for other MMPs (exception MMP-8), and has established in vivo efficacy in inflammation models. Coadministration of WAY-644 to hyperlipidemic apoE−/− mice during ANGII infusion (1.44 mg/kg) for 28d alters the severity of AngII-induced AAAs as measured by changes in abdominal aortic wet weights and typical AAA classification. As expected, plasma MMP-12 protease activity measured by FRET analysis was inhibited. RNA profiling of abdominal aortic aneurysm tissue characterizes ANGII-induced AAA expansion driven by macrophage infiltration, destructive MMP production and attenuation by MMP-12 inhibition. The transcription of a subset of proinflammatory genes activated with ANGII treatment was repressed by the inhibitor. These genes include quantitative markers of macrophage accumulation in the vessel wall, CD68, MCP1/CCL2, CCR2, MMP-12, and Csf1. Associated reductions in gene markers for inflammation and oxidative stress, ie., heme oxidase (HO), nitric oxide synthase (nos2), Ikbkb, and Stat3 also correlate with MMP-12 antagonism. These changes occur in the absence of lipid changes (TC or TG), or quantitative changes in aortic arch lesions in the ANGII-infused animals. The findings support a mechanism whereby MMP-12 metalloelastase inactivation reduces macrophage recruitment to aneurysmal lesion sites, to lessen activated-macrophage expression of proinflammatory cytokines that figure prominently in vascular wall destruction and the pathogenesis of AAAs.

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Adipocyte in vascular wall can induce the rupture of abdominal aortic aneurysm

Scientific Reports ◽

10.1038/srep31268 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 22

Author(s):

Hirona Kugo ◽

Nobuhiro Zaima ◽

Hiroki Tanaka ◽

Youhei Mouri ◽

Kenichi Yanagimoto ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Vascular Wall ◽

Abdominal Aortic

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Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II–Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm

Hypertension ◽

10.1161/hypertensionaha.118.11144 ◽

2018 ◽

Vol 72 (1) ◽

pp. 128-138 ◽

Cited By ~ 8

Author(s):

Surawee Chuaiphichai ◽

Victoria S. Rashbrook ◽

Ashley B. Hale ◽

Lucy Trelfa ◽

Jyoti Patel ◽

...

Keyword(s):

Blood Pressure ◽

Abdominal Aortic Aneurysm ◽

Endothelial Cell ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Vascular Remodeling ◽

Abdominal Aortic

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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.

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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.

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