Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Polymorphisms in a Caucasian Population with Abdominal Aortic Aneurysm

Objective: Abdominal aortic aneurysm is characterized by the progressive loss of aortic integrity and accumulation of inflammatory cells primarily macrophages. We previously reported that global deletion of matricellular protein TSP1 (thrombospondin-1) protects mice from aneurysm formation. The objective of the current study is to investigate the cellular and molecular mechanisms underlying TSP1’s action in aneurysm. Approach and Results: Using RNA fluorescent in situ hybridization, we identified macrophages being the major source of TSP1 in human and mouse aneurysmal tissues, accounting for over 70% of cells that actively expressed Thbs1 mRNA. Lack of TSP1 in macrophages decreased solution-based gelatinase activities by elevating TIMP1 (tissue inhibitor of metalloproteinases-1) without affecting the major MMPs (matrix metalloproteinases). Knocking down Timp1 restored the ability of Thbs1 − /− macrophages to invade matrix. Finally, we generated Thbs1 flox/flox mice and crossed them with Lyz2-cre mice. In the CaCl 2 -induced model of abdominal aortic aneurysm, lacking TSP1 in myeloid cells was sufficient to protect mice from aneurysm by reducing macrophage accumulation and preserving aortic integrity. Conclusions: TSP1 contributes to aneurysm pathogenesis, at least in part, by suppressing TIMP1 expression, which subsequently enables inflammatory macrophages to infiltrate vascular tissues.

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Decreased tissue inhibitor of metalloproteinases (TIMP) in abdominal aortic aneurysm tissue: A preliminary report

Journal of Surgical Research ◽

10.1016/0022-4804(91)90058-t ◽

1991 ◽

Vol 50 (6) ◽

pp. 653-657 ◽

Cited By ~ 62

Author(s):

Colleen M. Brophy ◽

William H. Marks ◽

Jeffrey M. Reilly ◽

M. David Tilson

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Preliminary Report ◽

Tissue Inhibitor Of Metalloproteinases ◽

Tissue Inhibitor ◽

Abdominal Aortic

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.106 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Chanwoo Kim ◽

Sandeep Kumar ◽

Dong Ju Son ◽

In-Hwan Jang ◽

Hanjoong Jo

Keyword(s):

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Therapeutic Strategy ◽

Vascular Wall ◽

Matrix Metalloproteases ◽

Tissue Inhibitor Of Metalloproteinase ◽

Cysteine Rich Protein ◽

Endogenous Inhibitors ◽

Abdominal Aortic

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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Salmonellosis associated with abdominal aortic aneurysm

Archives of Internal Medicine ◽

10.1001/archinte.134.6.1095 ◽

1974 ◽

Vol 134 (6) ◽

pp. 1095-1098 ◽

Cited By ~ 5

Author(s):

Y. S. Kanwar

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Abdominal Aortic

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Current evidence and prospects for medical treatment of abdominal aortic aneurysms

VASA ◽

10.1024/0301-1526.34.4.217 ◽

2005 ◽

Vol 34 (4) ◽

pp. 217-223 ◽

Cited By ~ 11

Author(s):

Diehm ◽

Schmidli ◽

Dai-Do ◽

Baumgartner

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Medical Treatment ◽

Endovascular Treatment ◽

Abdominal Aortic Aneurysms ◽

Aortic Aneurysms ◽

Current Evidence ◽

Significant Morbidity ◽

Abdominal Aortic ◽

Risk Of Rupture

Abdominal aortic aneurysm (AAA) is a potentially fatal condition with risk of rupture increasing as maximum AAA diameter increases. It is agreed upon that open surgical or endovascular treatment is indicated if maximum AAA diameter exceeds 5 to 5.5cm. Continuing aneurysmal degeneration of aortoiliac arteries accounts for significant morbidity, especially in patients undergoing endovascular AAA repair. Purpose of this review is to give an overview of the current evidence of medical treatment of AAA and describe prospects of potential pharmacological approaches towards prevention of aneurysmal degeneration of small AAAs and to highlight possible adjunctive medical treatment approaches after open surgical or endovascular AAA therapy.

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Influence of preoperative statins and aspirin administration on biological and magnetic resonance imaging properties in patients with abdominal aortic aneurysm

VASA ◽

10.1024/0301-1526/a000895 ◽

2020 ◽

pp. 1-9

Author(s):

Milos Sladojevic ◽

Petar Zlatanovic ◽

Zeljka Stanojevic ◽

Igor Koncar ◽

Sasenka Vidicevic ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Abdominal Aortic Aneurysm ◽

Magnetic Resonance ◽

Aortic Aneurysm ◽

Signal Intensity ◽

Psoas Muscle ◽

Resonance Imaging ◽

Maximal Diameter ◽

Aneurysm Wall ◽

Abdominal Aortic

Summary: Background: Main objective of this study was to evaluate the influence of statins and/or acetylsalicylic acid on biochemical characteristics of abdominal aortic aneurysm (AAA) wall and intraluminal thrombus (ILT). Patients and methods: Fifty patients with asymptomatic infrarenal AAA were analyzed using magnetic resonance imaging on T1w sequence. Relative ILT signal intensity (SI) was determined as a ratio between ILT and psoas muscle SI. Samples containing the full ILT thickness and aneurysm wall were harvested from the anterior surface at the level of the maximal diameter. The concentration of enzymes such as matrix metalloproteinase (MMP) 9, MMP2 and neutrophil elastase (NE/ELA) were analyzed in ILT and AAA wall; while collagen type III, elastin and proteoglycan 4 were analyzed in harvested AAA wall. Oxidative stress in the AAA wall was assessed by catalase and malondialdehyde activity in tissue samples. Results: Relative ILT signal intensity (1.09 ± 0.41 vs 0.89 ± 0.21, p = 0.013) were higher in non-statin than in statin group. Patients who were taking aspirin had lower relative ILT area (0.89 ± 0.19 vs 1.13. ± 0.44, p = 0.016), and lower relative ILT signal intensity (0.85 [0.73–1.07] vs 1.01 [0.84–1.19], p = 0.021) compared to non-aspirin group. There were higher concentrations of elastin in AAA wall among patients taking both of aspirin and statins (1.21 [0.77–3.02] vs 0.78 (0.49–1.05) ng/ml, p = 0.044) than in patients who did not take both of these drugs. Conclusions: Relative ILT SI was lower in patients taking statin and aspirin. Combination of antiplatelet therapy and statins was associated with higher elastin concentrations in AAA wall.

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