| 1. |
- Folkersen, Lasse, et al.
(författare)
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Unraveling Divergent Gene Expression Profiles in Bicuspid and Tricuspid Aortic Valve Patients with Thoracic Aortic Dilatation: The ASAP Study
- 2011
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Ingår i: Molecular Medicine. - : Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 17:11-12, s. 1365-1373
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Tidskriftsartikel (refereegranskat)abstract
- Thoracic aortic aneurysm (TAA) is a common complication in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart disorder. For unknown reasons TAA occurs at a younger age, with a higher frequency in BAV patients than in patients with a tricuspid aortic valve (TAV), resulting in an increased risk for aortic dissection and rupture. To investigate the increased TAA incidence in BAV patients, we obtained tissue biopsy samples from nondilated and dilated aortas of 131 BAV and TAV patients. Global gene expression profiles were analyzed from controls and from aortic intima-media and adventitia of patients (in total 345 samples). Of the genes found to be differentially expressed with dilation, only a few (less than4%) were differentially expressed in both BAV and TAV patients. With the use of gene set enrichment analysis, the cell adhesion and extracellular region gene ontology sets were identified as common features of TAA in both BAV and TAV patients. Immune response genes were observed to be particularly overexpressed in the aortic media of dilated TAV samples. The divergent gene expression profiles indicate that there are fundamental differences in TAA etiology in BAV and TAV patients. Immune response activation solely in the aortic media of TAV patients suggests that inflammation is involved in TAA formation in TAV but not in BAV patients. Conversely, genes were identified that were only differentially expressed with dilation in BAV patients. The result has bearing on future clinical studies in which separate analysis of BAV and TAV patients is recommended.
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| 2. |
- Paloschi, Valentina, et al.
(författare)
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Impaired Splicing of Fibronectin Is Associated With Thoracic Aortic Aneurysm Formation in Patients With Bicuspid Aortic Valve
- 2011
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 31:3, s. 691-697
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients.METHODS AND RESULTS:The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (ρ=0.58) but not in BAV (ρ=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-β treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-β signaling pathway may explain the impaired EDA inclusion in BAV patients.CONCLUSIONS:Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.
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| 3. |
- Bertorello, Alejandro M., et al.
(författare)
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Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)
- 2015
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Ingår i: Circulation Research. - : American Heart Association. - 0009-7330 .- 1524-4571. ; 116:4, s. 642-U190
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-beta 1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1+/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-beta 1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-beta 1-signaling inhibition.
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| 4. |
- Di Gennaro, Antonio, et al.
(författare)
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Increased expression of leukotriene C-4 synthase and predominant formation of cysteinyl-leukotrienes in human abdominal aortic aneurysm
- 2010
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:49, s. 21093-21097
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Tidskriftsartikel (refereegranskat)abstract
- Leukotrienes (LTs) are arachidonic acid-derived lipid mediators involved in the pathogenesis and progression of diverse inflammatory disorders. The cysteinyl-leukotrienes LTC4, LTD4, and LTE4 are important mediators of asthma, and LTB4 has recently been implicated in atherosclerosis. Here we report that mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTC4 synthase (LTC4S), are significantly increased in the wall of human abdominal aortic aneurysms (AAAs). In contrast, mRNA levels of LTA(4) hydrolase, the enzyme responsible for the biosynthesis of LTB4, are not increased. Immunohistochemical staining of AAA wall revealed focal expression of 5-LO, FLAP, and LTC4S proteins in the media and adventitia, localized in areas rich in inflammatory cells, including macrophages, neutrophils, and mast cells. Human AAA wall tissue converts arachidonic acid and the unstable epoxide LTA(4) into significant amounts of cysteinyl-leukotrienes and to a lesser extent LTB4. Furthermore, challenge of AAA wall tissue with exogenous LTD4 increases the release of matrix metalloproteinase (MMP) 2 and 9, and selective inhibition of the CysLT1 receptor by montelukast blocks this effect. The increased expression of LTC4S, together with the predominant formation of cysteinyl-leukotrienes and effects on MMPs production, suggests a mechanism by which LTs may promote matrix degradation in the AAA wall and identify the components of the cysteinyl-leukotriene pathway as potential targets for prevention and treatment of AAA.
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| 5. |
- Folkesson, Maggie, et al.
(författare)
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Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms
- 2015
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Ingår i: Thrombosis and Haemostasis. - : SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN. - 0340-6245 .- 2567-689X. ; 114:6, s. 1165-1174
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Tidskriftsartikel (refereegranskat)abstract
- The intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) has been suggested to damage the underlying aortic wall, but previous work found scant activity of soluble proteases in the abluminal layer of the ILT, adjacent to the aneurysm. We hypothesised that transmembrane proteases carried by membrane microvesicles (MV) from dying cells remain active in the abluminal ILT. ILTs and AAA segments collected from 21 patients during surgical repair were assayed for two major transmembrane proteases, ADAM10 (a disintegrin and metalloprotease-10) and ADAM17. We also exposed cultured cells to tobacco smoke and assessed ADAM10 and ADAM17 expression and release on MVs. Immunohistochemistry showed abundant ADAM10 and ADAM17 protein in the ILT and underlying aneurysmal aorta. Domain-specific antibodies indicated both transmembrane and shed ADAM17. Importantly, ADAM10 and ADAM 17 in the abluminal ILT were enzymatically active. Electron microscopy of abluminal ILT and aortic wall showed MVs with ADAM10 and ADAM17. By flow cytometry, ADAM-positive microvesicles from abluminal ILT carried the neutrophil marker CD66, but not the platelet marker CD61. Cultured HL60 neutrophils exposed to tobacco smoke extract showed increased ADAM10 and ADAM17 content, cleavage of these molecules into active forms, and release of MVs carrying mature ADAM10 and detectable ADAM17. In conclusion, our results implicate persistent, enzymatically active ADAMs on MVs in the abluminal ILT, adjacent to the aneurysmal wall. The production of ADAM10- and ADAM17-positive MVs from smoke-exposed neutrophils provides a novel molecular mechanism for the vastly accelerated risk of AAA in smokers.
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| 6. |
- Jackson, Veronica, et al.
(författare)
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Matrix metalloproteinase 14 and 19 expression is associated with thoracic aortic aneurysms
- 2012
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier. - 0022-5223 .- 1097-685X. ; 144:2, s. 459-466
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:It is hypothesized that an altered turnover of extracellular matrix mediated by matrix metalloproteinases (MMPs) is present in thoracic aortic aneurysms. Here, we analyzed the occurrence of MMPs and MMP inhibitors in ascending aortic aneurysms in patients with bicuspid and tricuspid aortic valves.METHODS:Expression of 23 MMPs and their inhibitors was measured in aortic intima/media and adventitia in 109 patients (40 tricuspid, 69 bicuspid, 68 with aortic diameter≥4.5 cm, and 41 with ≤4.0 cm) using Affymetrix Exon arrays (Affymetrix, Santa Clara, Calif). Gene expression was confirmed by quantitative real-time polymerase chain reaction. Principal components analysis was used to study differences in gene expression. Immunohistochemistry was used to study protein expression.RESULTS:We detected messenger RNA expression for gelatinases (MMP2 and MMP9), stromelysin 3 (MMP11), all membrane bound MMPs (MMP14, MMP15, MMP16, MMP17, MMP24, MMP25), MMP19, MMP21, and MMP28 in ascending aorta. No expression of collagenases was detected. Principal components analysis showed that changes in mRNA expression between dilated and nondilated aorta were mainly detected in patients with tricuspid aortic valves. MMP14 and MMP19 showed higher expression in dilated aortas and MMP19 expression correlated positively to maximal aortic diameter in patients with tricuspid aortic valves (Rho=0.61, P=.004, and Rho=0.57, P=.008, using raw and body surface area-corrected aortic diameter, respectively). Immunohistochemical staining demonstrated increased medial expression of MMP14 and MMP19 in dilated aorta.CONCLUSIONS:The present study identifies MMP14 and MMP19 as proteolytic enzymes potentially involved in aneurysm formation in the ascending aorta of patients with tricuspid aortic valves
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| 7. |
- Kolak, Maria, et al.
(författare)
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Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity
- 2007
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:8, s. 1960-1968
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.RESEARCH DESIGN AND METHODS: A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.RESULTS: Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.CONCLUSIONS: Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.
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| 8. |
- Ovchinnikova, Olga, et al.
(författare)
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T-Cell Activation Leads to Reduced Collagen Maturation in Atherosclerotic Plaques of Apoe−/− Mice
- 2009
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Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 174:2, s. 693-700
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Tidskriftsartikel (refereegranskat)abstract
- Rupture of the collagenous, fibrous cap of an atherosclerotic plaque commonly causes thrombosis. Activated immune cells can secrete mediators that jeopardize the integrity of the fibrous cap. This study aimed to determine the relationship between T-cell-mediated inflammation and collagen turnover in a mouse model of experimental atherosclerosis. Both Apoe(-/-) x CD4dnT beta RII mice with defective transforming growth factor-beta receptors in T cells (and hence released from tonic suppression of T-cell activation) and lesion size-matched Apoe(-/-) mice were used. Picrosirius red staining showed a lower content of thick mature collagen fibers in lesions of Apoe(-/-) x CD4dnT beta RII mice, although both groups had similar levels of procollagen type I or M mRNA and total collagen content in lesions. Analysis of both gene expression and protein content showed a significant decrease of lysyl oxidase, the extracellular enzyme needed for collagen cross-linking, in aortas of Apoe(-/-) - CD4dnT beta RII mice. T-cell-driven inflammation provoked a selective and limited increase in the expression of proteinases that catabolize the extracellular matrix. Atheromata of Apoe(-/-) - CD4dnT beta RII mice had increased levels of matrix metalloproteinase-13 and cathepsin S mRNAs and of the active form of cathepsin S protein but no increase was detected in collagen fragmentation. our results suggest that exaggerated T-cell-driven inflammation limits collagen maturation in the atherosclerotic plaque while having little effect on collagen degradation.
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| 9. |
- Villard, Christina, et al.
(författare)
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Biomarkers for Abdominal Aortic Aneurysms From a Sex Perspective
- 2012
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Ingår i: Gender Medicine. - : Elsevier. - 1550-8579 .- 1878-7398. ; 9:4, s. 259-266
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Abdominal aortic aneurysms (AAAs) differ in men and women. Women are older at diagnosis, have a higher risk of rupture, and worse outcome after surgery compared with men. The higher occurrence of AAAs in men accounts for the dominance of men in biomarker analyses.OBJECTIVE:The primary aim of this study was to investigate levels of established biomarkers for AAA in men and women, and the secondary aim was to compare biomarker levels in women with and without AAAs.METHODS:In this prospective case-control study, blood samples were collected from 16 women and 18 men with AAAs ≥5.5 cm, from 20 women with AAAs <5.5 cm, and from 18 women with peripheral artery disease (PAD). Plasma concentrations of matrix metalloproteinase (MMP) -2, -9, and -13; tissue inhibitor of MMP-1 (TIMP-1); plasminogen activator inhibitor 1 (PAI-1); high-sensitivity C-reactive protein (hsCRP); and estradiol levels were analyzed by ELISA. An ultrasound examination was performed in women with PAD to exclude an AAA.RESULTS:Age and other comorbid conditions were similar between men and women with AAAs. Women with AAAs had higher levels of MMP-9 compared with men with equally large AAAs (42.8 ng/mL vs 36.2 ng/mL, P = 0.036) and lower levels of estradiol (30.0 pmoL vs 86.5 pmol/L, P < 0.001). Women with AAAs had lower levels of MMP-9 compared with women without (59.5 ng/mL vs 132.6 ng/mL, P = 0.010). There was no significant difference in the plasma levels of MMP-2, MMP-13, hsCRP, PAI-1, TIMP-1, and estradiol between women with and without AAAs.CONCLUSION:The higher levels of MMP-9 in women compared with men with equally large AAAs could suggest that MMP-9 is a biomarker related to the sex differences in aneurysm development. The lower levels of estradiol in women with AAAs compared with men suggest that the possible protective effect of endogenous estrogen cannot be explained by a difference in circulating levels of estradiol.
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| 10. |
- Vorkapic, Emina, et al.
(författare)
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Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm
- 2016
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 249, s. 101-109
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Tidskriftsartikel (refereegranskat)abstract
- AbstractBackground Abdominal aortic aneurysm (AAA) is characterized by vascular remodeling with increased infiltration of inflammatory cells and apoptosis/modulation of vascular smooth muscle cells (SMCs). Imatinib is a selective inhibitor of several tyrosine kinases, including PDGF receptors, Abl, and c-kit. The objective of this study was to characterize the potential protective role of imatinib on AAA development and the molecular mechanisms involved. Methods Male ApoE−/− mice were infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Daily treatment with 10 mg/kg imatinib, or tap water as control, was provided via gavage for 4 weeks. Results Treatment with imatinib was found to decrease the aortic diameter and vessel wall thickness, mediated by multiple effects. Imatinib treatment in AngII infused mice resulted in a reduced cellular infiltration of CD3ε positive T lymphocytes by 86% and reduced gene expression of mast cell chymase by 50% compared with AngII infused mice lacking imatinib. Gene expression analysis of SMC marker SM22α demonstrated an increase by 48% together with a more intact medial layer after treatment with imatinib as evaluated with SM22α immunostaining. Conclusion Present findings highlight the importance of tyrosine kinase pathways in the development of AAA. Our results show, that imatinib treatment inhibits essential mast cell, T lymphocyte and SMC mediated processes in experimental AAA. Thus, our results support the idea that tyrosine kinase inhibitors may be useful in the treatment of pathological vascular inflammation and remodeling in conditions like AAA.
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