Expression of matrix metalloproteinases, their tissue inhibitors, and osteopontin in the wall of thoracic and abdominal aortas with dilatative pathology☆

Lesauskaitė, Vaiva; Epistolato, Maria Carmela; Castagnini, Marta; Urbonavičius, Sigitas; Tanganelli, Piero

doi:10.1016/j.humpath.2006.03.017

Cited by 41 publications

(41 citation statements)

References 26 publications

(31 reference statements)

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“…35 SPP1 was upregulated in human AAAs and thoracic aortic aneurysms. 36 Moreover, SPP1 was increasingly upregulated from 30-to 45-fold in swine carotid artery aneurysms. 37 Our study is the first to provide evidence of SPP1 overexpression (35-fold increase) in human IAs.…”

Section: Shi Et Al Genomics Of Human Intracranial Aneurysmsmentioning

confidence: 97%

Genomics of Human Intracranial Aneurysm Wall

Shi

Awad

Jafari

et al. 2009

Stroke

107

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Background and Purpose-The pathogenesis of intracranial aneurysms (IAs) remains elusive. Most studies have focused on individual genes, or a few interrelated genes or products, at a time in human IA. However, a broad view of pathologic mechanisms has not been investigated by identifying pathogenic genes and their interaction in networks. Our study aimed to analyze global gene expression patterns in the IA wall. Methods-To our knowledge, our group was the first to perform Illumina microarray analysis on human IA via comparison of aneurysm wall and superficial temporal artery tissues from 6 consecutive patients. We adopted stringent statistical criteria to the individual genes; genes with a false discovery rate Ͻ0.01 and Ͼ2-fold change were selected as differentially expressed. To identify the overrepresented biologic pathways with the differentially expressed genes, we performed hypergeometric testing of the genes selected by relaxed criteria of PϽ0.01 and fold change Ͼ1.5. Results-There are 326 distinct differentially expressed genes between IA and superficial temporal artery tissues (Ͼ2-fold change) with a false discovery rate Ͻ0.01. Analysis of the Kyoto Encyclopedia of Genes and Genomes pathways revealed the most impacted functional pathways: focal adhesion, extracellular matrix receptor interaction, and cell communication. Analysis of the Gene Ontology also supported the involvement of another 2 potentially important pathways: inflammatory response and apoptosis. Conclusions-The differentially expressed genes in the aneurysm wall may shed light on aneurysm pathobiology and provide novel targets for therapeutic intervention. These data will help generate hypotheses for future studies. (Stroke.

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Section: Shi Et Al Genomics Of Human Intracranial Aneurysmsmentioning

confidence: 97%

Genomics of Human Intracranial Aneurysm Wall

Shi

Awad

Jafari

et al. 2009

Stroke

107

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“…In AAA, MMP-9 expression in inflammatory cells is higher than in smooth muscle cells (SMCs), whereas MMP-2 demonstrates higher expression in SMCs than in inflammatory cells [5]. Leukocyte-derived MMP-9 is associated with aortic wall degeneration and aneurysm formation [6].…”

Section: Introductionmentioning

confidence: 99%

MMP-9, Homocysteine and CRP Circulating Levels Are Associated with Intraluminal Thrombus Thickness of Abdominal Aortic Aneurysms–New Implication of the Old Biomarkers

et al. 2011

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Abstract. Background: Abdominal aortic aneurysms (AAAs) are characterized by presence of high proteolytic activity, atherosclerotic lesions, extensive transmural inflammation and the presence of variably sized and shaped intraluminal thrombus (ILT). Therefore, we evaluated a possible association between plasma matrix metalloproteinase-9 (MMP-9), homocysteine (Hcy), high-sensitivity C-reactive protein (hsCRP) levels and ILT thickness in patients with AAA. Methods: Plasma concentrations of MMP-9, Hcy and hsCRP were determined and ILT thickness was measured in 71 patients with AAA. They were divided into 2 groups according to ILT thickness: 34 patients with ILT mean thickness 9 mm and 37 patients with ILT < 9 mm. Results: Plasma MMP-9 and CRP concentrations in patients with thin ILT were significantly higher than in group with thick ILT (medians 610 vs. 485 ng/mL, p = 0.00003, and 7.7 vs. 3.3 mg/L, p < 0.00001, respectively). In contrast, plasma Hcy concentrations in patients with thin ILT were significantly lower than in the group with thick ILT (medians 14.3 vs. 19.2 µmol/L, p < 0.00001). Multiple regression models adjusted for age and AAA diameter showed that thin ILT is an independent predictor of high MMP-9 and CRP concentrations, while thick ILT predicts high Hcy concentrations. Conclusions: Association of higher plasma levels of MMP-9 and CRP with thin ILT may be related to two phenomena: thin thrombi convey more elastolysis-stimulating factors from blood to the AAA wall and thin thrombi convey more factors involved in proteolysis and inflammation from AAA wall to blood. The association of thin ILT with lower plasma Hcy concentrations may be related to the role of Hcy as a prothrombotic marker and needs further research.

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“…The metal-dependent MMP-2, 7, 8, 9, 10, 12, and 14 can degrade elastin and/or play a role in aortic aneurisms [12][13][14][15]. Furthermore, MMP-9 or MMP-12 deficiency reduced elastin fragmentation within atherosclerotic lesions in hypercholesterolemic mice [14] or reduced CaCl 2 -induced aneurism formation [12,16].…”

Section: Introductionmentioning

confidence: 99%

“…MMPs are activated proteolytically by urokinase plasminogen activator (uPA), or without cleavage by SIBLINGs (small integrin-binding ligand N-linked glycoproteins) such as osteopontin [17]. uPA deficiency reduced aneurism formation [10] while osteopontin is upregulated in aortic aneurisms [15]. Tissue inhibitor of metalloproteinases (TIMP) 1 binds and inactivates MMPs, while TIMP-2 protects MMPs from inactivation by TIMP-1; TIMP-1 overexpression [18] and TIMP-2 [19] deficiency reduced aneurism formation in mice.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

Tittiger

Knutsen

et al. 2008

Molecular Genetics and Metabolism

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Mucopolysaccharidosis I (MPS I), known as Hurler syndrome in the severe form, is a lysosomal storage disease due to -L-iduronidase (IDUA) deficiency. It results in fragmentation of elastin fibers in the aorta and heart valves via mechanisms that are unclear, but may result from the accumulation of the glycosaminoglycans heparan and dermatan sulfate. Elastin fragmentation causes aortic dilatation and valvular insufficiency, which can result in cardiovascular disease. The pathophysiology of aortic disease was evaluated in MPS I mice. MPS I mice have normal elastic fiber structure and aortic compliance at early ages, which suggests that elastin assembly is normal. Elastin fragmentation and aortic dilatation are severe at 6 months, which is temporally associated with marked increases in mRNA and enzyme activity for two elastin-degrading proteins, matrix metalloproteinase-12 (MMP-12) and cathepsin S. Upregulation of these genes likely involves activation of STAT proteins, which may be induced by structural stress to smooth muscle cells from accumulation of glycosaminoglycans in lysosomes. Neonatal intravenous injection of a retroviral vector normalized MMP-12 and cathepsin S mRNA levels and prevented aortic disease. We conclude that aortic dilatation in MPS I mice is likely due to degradation of elastin by MMP-12 and/or cathepsin S. This aspect of disease might be ameliorated by inhibition of the signal transduction pathways that upregulate expression of elastase proteins, or by inhibition of elastase activity. This could result in a treatment for patients with MPS I, and might reduce aortic aneurism formation in other disorders.

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Expression of matrix metalloproteinases, their tissue inhibitors, and osteopontin in the wall of thoracic and abdominal aortas with dilatative pathology☆

Cited by 41 publications

References 26 publications

Genomics of Human Intracranial Aneurysm Wall

Genomics of Human Intracranial Aneurysm Wall

MMP-9, Homocysteine and CRP Circulating Levels Are Associated with Intraluminal Thrombus Thickness of Abdominal Aortic Aneurysms–New Implication of the Old Biomarkers

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

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