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ABSTRACT: Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/ inhibition causes hypertension, whereas deficiency/ inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/ inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis.
Current Atherosclerosis Reports 05/2013; 15(5):320. · 2.66 Impact Factor
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ABSTRACT: Atherosclerosis is a major risk factor for cardiovascular disease (CVD) and stroke. Galectin-3 is a carbohydrate-binding lectin implicated in the pathophysiology of CVD and is highly expressed within atherosclerotic lesions in mice and humans. The object of this present study was to use genetic deletion and pharmacological inhibition in a well-characterized mouse model of atherosclerosis to determine the role of galectin-3 in plaque development. Apolipoprotein-E/galectin-3 knockout mice were generated and fed a high-cholesterol "western" diet. Galectin-3 deletion had no consistent effect on the serum lipid profile but halved atherosclerotic lesion formation in the thoracic aorta (57% reduction), the aortic arch (50% reduction) and the brachiocephalic arteries. The aortic plaques were smaller, with reduced lipid core and less collagen. In apolipoprotein E-deficient (ApoE-/-) mice, there was a switch from high inducible nitric oxide expression in early lesions (6 weeks) to arginase-1 expression in later lesions (20 weeks), which was reversed in ApoE-/-/gal-3-/- mice. Administration of modified citrus pectin, an inhibitor of galectin-3, during the latter stage of the disease reduced plaque volume. We conclude that inhibiting galectin-3 causes decreased atherosclerosis. Strategies to inhibit galectin-3 function may reduce plaque progression and potentially represent a novel therapeutic strategy in the treatment of atherosclerotic disease.
Glycobiology 02/2013; · 3.58 Impact Factor
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ABSTRACT: 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1; EC 1.1.1.146) generates active glucocorticoids from inert 11-keto metabolites. However, it can also metabolise alternative substrates, including 7β-hydroxy- and 7-keto-cholesterol (7βOHC, 7KC). This has been demonstrated in vitro but its consequences in vivo are uncertain. We used knockout mice to investigate the contribution of 11βHSD1 to the balance of circulating levels of 7KC and 7βOHC in vivo, and dissected in vitro the kinetics of the interactions between oxysterols and glucocorticoids for metabolism by the mouse enzyme. Circulating levels of 7KC and 7βOHC in mice were 91.3±22.3 and 22.6±5.7nM respectively, increasing to 1240±220 and 406±39nM in ApoE(-/-) mice receiving atherogenic western diet. Disruption of 11βHSD1 in mice increased (p<0.05) the 7KC/7βOHC ratio in plasma (by 20%) and also in isolated microsomes (2 fold). The 7KC/7βOHC ratio was similarly increased when NADPH generation was restricted by disruption of hexose-6-phosphate dehydrogenase. Reduction and oxidation of 7-oxysterols by murine 11βHSD1 proceeded more slowly and substrate affinity was lower than for glucocorticoids. In vitro 7βOHC was a competitive inhibitor of oxidation of corticosterone (Ki=0.9μM), whereas 7KC only weakly inhibited reduction of 11-dehydrocorticosterone. However supplementation of 7-oxysterols in cultured cells, secondary to cholesterol loading, preferentially slowed reduction of glucocorticoids, rather than oxidation. Thus, in mouse, 11βHSD1 influenced the abundance and balance of circulating and tissue levels of 7βOHC and 7KC, promoting reduction of 7KC. In health, 7-oxysterols are unlikely to regulate glucocorticoid metabolism. However, in hyperlipidaemia, 7-oxysterols may inhibit glucocorticoid metabolism and modulate signaling through corticosteroid receptors.
Biochemical pharmacology 02/2013; · 4.25 Impact Factor
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Tiina Kipari, Patrick W F Hadoke,
Javaid Iqbal,
Tak-Yung Man,
Eileen Miller,
Agnes E Coutinho,
Zhenguang Zhang,
Katie M Sullivan,
Tijana Mitic,
Dawn E W Livingstone, [......],
Kay Samuel,
Christopher I White,
M Amine Bouhlel,
Giulia Chinetti-Gbaguidi,
Bart Staels,
Ruth Andrew,
Brian R Walker,
John S Savill,
Karen E Chapman,
Jonathan R Seckl
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ABSTRACT: 11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11β-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11β-HSD1 inhibitor or crossed with 11β-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11β-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11β-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11β-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11β-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.-Kipari, T., Hadoke, P. W. F., Iqbal, J., Man, T. Y., Miller, E., Coutinho, A. E., Zhang, Z., Sullivan, K. M., Mitic, T., Livingstone, D. E. W., Schrecker, C., Samuel, K., White, C. I., Bouhlel, M. A., Chinetti-Gbaguidi, G., Staels, B., Andrew, R., Walker, B. R., Savill, J. S., Chapman, K. E., Seckl, J. R. 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis.
The FASEB Journal 01/2013; · 5.71 Impact Factor
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ABSTRACT: Exogenous glucocorticoids inhibit neointimal proliferation in animals. We aimed to test the hypothesis that endogenous glucocorticoids influence neointimal proliferation; this may be mediated by effects on systemic risk factors or locally in vessels and modulated by either adrenal secretion or enzymes expressed in vessels that mediate local inactivation [11β-hydroxysteroid dehydrogenase type II (11β-HSD2) in endothelium] or regeneration [11β-hydroxysteroid dehydrogenase type I (11β-HSD1) in smooth muscle] of glucocorticoids. Femoral artery wire angioplasty was conducted in C57BL/6J, Apo-E(-/-), 11β-HSD1(-/-), Apo-E, 11β-HSD1(-/-) (double knockout), and 11β-HSD2(-/-) mice after glucocorticoid administration, adrenalectomy, glucocorticoid or mineralocorticoid receptor antagonism, or selective 11β-HSD1 inhibition. In C57BL/6J mice, neointimal proliferation was reduced by systemic or local glucocorticoid administration, unaffected by adrenalectomy, reduced by the mineralocorticoid receptor antagonist eplerenone, and increased by the glucocorticoid receptor antagonist RU38486. 11β-HSD2 deletion had no effect on neointimal proliferation, with or without eplerenone. 11β-HSD1 inhibition or deletion had no effect in chow-fed C57BL/6J mice but reduced neointimal proliferation in Apo-E(-/-) mice on Western diet. Reductions in neointimal size were accompanied by reduced macrophage and increased collagen content. We conclude that pharmacological administration of glucocorticoid receptor agonists or of mineralocorticoid receptor antagonists may be useful in reducing neointimal proliferation. Endogenous corticosteroids induce beneficial glucocorticoid receptor activation and adverse mineralocorticoid receptor activation. However, manipulation of glucocorticoid metabolism has beneficial effects only in mice with exaggerated systemic risk factors, suggesting effects mediated primarily in liver and adipose rather than intravascular glucocorticoid signaling. Reducing glucocorticoid action with 11β-HSD1 inhibitors that are being developed for type 2 diabetes appears not to risk enhanced neointimal proliferation.
Endocrinology 11/2012; · 4.46 Impact Factor
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ABSTRACT: The atherogenic 7-oxysterols, 7-ketocholesterol (7-KC) and 7β-hydroxycholesterol (7βOHC), can directly impair arterial function. Inter-conversion of 7-KC and 7βOHC has recently been shown as a novel role for the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Since this enzyme is expressed in vascular smooth muscle cells, we addressed the hypothesis that inter-conversion of 7-KC and 7βOHC by 11β-HSD1 may contribute to regulation of arterial function. Incubation (4-24 h) of aortic rings with either 7-KC (25 μM) or 7βOHC (20 μM) had no effect on endothelium-dependent (acetylcholine) or -independent (sodium nitroprusside) relaxation. In contrast, exposure to 7-KC (but not to 7βOHC) attenuated noradrenaline-induced contraction (E(max)) after 4 h (0.78 ± 0.28 vs 0.40 ± 0.08 mN/mm; p < 0.05) and 24 h (2.28 ± 0.34 vs 1.56 ± 0.48 mN/mm; p < 0.05). Both 7-oxysterols were detected by GCMS in the aortic wall of chow-fed C57Bl6/J mice, with concentrations of 7-KC (1.41 ± 0.81 ng/mg) higher (p = 0.05) than 7βOHC (0.16 ± 0.06 ng/mg). In isolated mouse aortic rings 11β-HSD1 was shown to act as an oxo-reductase, inter-converting 7-KC and 7βOHC. This activity was lost in aorta from 11β-HSD1(-/-) mice, which had low oxysterol levels. Renal homogenates from 11β-HSD1(-/-) mice were used to confirm that the type 2 isozyme of 11β-HSD does not inter-convert 7-KC and 7βOHC. These results demonstrate that 7-KC has greater effects than 7βOHC on vascular function, and that 11β-HSD1 can inter-convert 7-KC and 7βOHC in the arterial wall, contributing to the regulation of 7-oxysterol levels and potentially influencing vascular function. This mechanism may be important in the cardioprotective effects of 11β-HSD1 inhibitors.
Biochimie 08/2012; · 3.02 Impact Factor
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ABSTRACT: The potent vasoconstrictor endothelin-1 (ET-1), acting on the endothelin-A (ETA) receptor, promotes intimal lesion formation following vascular injury. The endothelin-B (ETB) receptor, which mediates nitric oxide release and ET-1 clearance in endothelial cells, may moderate lesion formation, but this is less clear. We used selective ET receptor antagonists and cell-specific deletion to address the hypothesis that ETB receptors in the endothelium inhibit lesion formation following arterial injury.
Neointimal proliferation was induced by wire or ligation injury to the femoral artery in mice treated with selective ETA (ABT-627) and/or ETB antagonists (A192621). Measurement of lesion formation by optical projection tomography and histology indicated that ETA blockade reduced lesion burden in both models. Although ETB blockade had little effect on ligation injury-induced lesion formation, after wire injury, blockade of the ETB receptor increased lesion burden (184% of vehicle; P < 0.05) and reversed the protective effects of an ETA antagonist. Selective deletion of ETB receptors from the endothelium, however, had no effect on neointimal lesion size.
These results are consistent with ETB receptor activation playing an important role in limiting neointimal lesion formation following acute vascular injury, but indicate that this protective effect is not mediated by those ETB receptors expressed by endothelial cells. These data support the proposal that selective ETA antagonists may be preferable to mixed ETA/ETB antagonists for targeting the arterial response to injury.
Cardiovascular research 03/2012; 95(1):19-28. · 5.80 Impact Factor
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Zoi Michailidou,
Sophie Turban,
Eileen Miller,
Xiantong Zou,
Joerg Schrader,
Peter J. Ratcliffe, Patrick W. F. Hadoke,
Brian R. Walker,
John P. Iredale,
Nicholas M. Morton,
Jonathan R. Seckl
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ABSTRACT: In obesity, rapidly expanding adipose tissue becomes hypoxic, precipitating inflammation, fibrosis, and insulin resistance.
Compensatory angiogenesis may prevent these events. Mice lacking the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid
dehydrogenase type 1 (11βHSD1−/−) have “healthier” adipose tissue distribution and resist metabolic disease with diet-induced obesity. Here we show that adipose
tissues of 11βHSD1−/− mice exhibit attenuated hypoxia, induction of hypoxia-inducible factor (HIF-1α) activation of the TGF-β/Smad3/α-smooth muscle
actin (α-SMA) signaling pathway, and fibrogenesis despite similar fat accretion with diet-induced obesity. Moreover, augmented
11βHSD1−/− adipose tissue angiogenesis is associated with enhanced peroxisome proliferator-activated receptor γ (PPARγ)-inducible expression
of the potent angiogenic factors VEGF-A, apelin, and angiopoietin-like protein 4. Improved adipose angiogenesis and reduced
fibrosis provide a novel mechanism whereby suppression of intracellular glucocorticoid regeneration promotes safer fat expansion
with weight gain.
Journal of Biological Chemistry 02/2012; 287(6):4188-4197. · 4.77 Impact Factor
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Patrick W F Hadoke
Journal of hypertension 01/2012; 30(1):40-1. · 4.02 Impact Factor
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Zoi Michailidou,
Sophie Turban,
Eileen Miller,
Xiantong Zou,
Joerg Schrader,
Peter J Ratcliffe, Patrick W F Hadoke,
Brian R Walker,
John P Iredale,
Nicholas M Morton,
Jonathan R Seckl
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ABSTRACT: In obesity, rapidly expanding adipose tissue becomes hypoxic, precipitating inflammation, fibrosis, and insulin resistance. Compensatory angiogenesis may prevent these events. Mice lacking the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1(-/-)) have "healthier" adipose tissue distribution and resist metabolic disease with diet-induced obesity. Here we show that adipose tissues of 11βHSD1(-/-) mice exhibit attenuated hypoxia, induction of hypoxia-inducible factor (HIF-1α) activation of the TGF-β/Smad3/α-smooth muscle actin (α-SMA) signaling pathway, and fibrogenesis despite similar fat accretion with diet-induced obesity. Moreover, augmented 11βHSD1(-/-) adipose tissue angiogenesis is associated with enhanced peroxisome proliferator-activated receptor γ (PPARγ)-inducible expression of the potent angiogenic factors VEGF-A, apelin, and angiopoietin-like protein 4. Improved adipose angiogenesis and reduced fibrosis provide a novel mechanism whereby suppression of intracellular glucocorticoid regeneration promotes safer fat expansion with weight gain.
Journal of Biological Chemistry 12/2011; 287(6):4188-97. · 4.77 Impact Factor
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Nicholas L Mills,
Mark R Miller,
Andrew J Lucking,
Jon Beveridge,
Laura Flint,
A John F Boere,
Paul H Fokkens,
Nicholas A Boon,
Thomas Sandstrom,
Anders Blomberg,
Rodger Duffin,
Ken Donaldson, Patrick W F Hadoke,
Flemming R Cassee,
David E Newby
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ABSTRACT: Exposure to road traffic and air pollution may be a trigger of acute myocardial infarction, but the individual pollutants responsible for this effect have not been established. We assess the role of combustion-derived-nanoparticles in mediating the adverse cardiovascular effects of air pollution.
To determine the in vivo effects of inhalation of diesel exhaust components, 16 healthy volunteers were exposed to (i) dilute diesel exhaust, (ii) pure carbon nanoparticulate, (iii) filtered diesel exhaust, or (iv) filtered air, in a randomized double blind cross-over study. Following each exposure, forearm blood flow was measured during intra-brachial bradykinin, acetylcholine, sodium nitroprusside, and verapamil infusions. Compared with filtered air, inhalation of diesel exhaust increased systolic blood pressure (145 ± 4 vs. 133 ± 3 mmHg, P< 0.05) and attenuated vasodilatation to bradykinin (P= 0.005), acetylcholine (P= 0.008), and sodium nitroprusside (P< 0.001). Exposure to pure carbon nanoparticulate or filtered exhaust had no effect on endothelium-dependent or -independent vasodilatation. To determine the direct vascular effects of nanoparticulate, isolated rat aortic rings (n= 6-9 per group) were assessed in vitro by wire myography and exposed to diesel exhaust particulate, pure carbon nanoparticulate and vehicle. Compared with vehicle, diesel exhaust particulate (but not pure carbon nanoparticulate) attenuated both acetylcholine (P< 0.001) and sodium-nitroprusside (P= 0.019)-induced vasorelaxation. These effects were partially attributable to both soluble and insoluble components of the particulate.
Combustion-derived nanoparticulate appears to predominately mediate the adverse vascular effects of diesel exhaust inhalation. This provides a rationale for testing environmental health interventions targeted at reducing traffic-derived particulate emissions.
European Heart Journal 07/2011; 32(21):2660-71. · 10.48 Impact Factor
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ABSTRACT: Exposure to air pollution containing diesel exhaust particulate (DEP) is linked to adverse cardiovascular events. This study tested the hypothesis that DEP not only causes direct endothelial cell injury, but also induces indirect endothelial cell activation via the release of soluble proinflammatory cytokines from macrophages. Human umbilical vein endothelial cells (HUVECs) and monocyte-derived macrophages (MDMs) were incubated with DEP (1-100 μg/ml; 24 h). Supernatants were analyzed for monocyte chemotactic protein (MCP)-1, IL6, IL8, and TNF-α. Indirect actions of DEP were investigated by incubating HUVECs with conditioned media from DEP-exposed MDMs in the presence and absence of the TNF-α inhibitor, etanercept. A modified Boyden chamber assay was used to determine whether HUVECs treated in this manner induced monocyte chemotaxis. Direct incubation with DEP induced a modest increase in MCP-1 concentration, but had no effect on IL-6 or IL-8 release from HUVECs. In contrast, direct treatment of MDMs with DEP had no effect on MCP-1, but elevated IL-8 and TNF-α concentrations. Incubation with conditioned media from DEP-exposed MDMs caused a dramatic amplification in MCP-1 and IL-6, but not IL-8, release from HUVECs. The potentiation of HUVEC activation was suppressed by TNF-α inhibition. MCP-1- and IL-6-containing HUVEC supernatants caused increased monocyte chemotaxis that was not inhibited by anti-MCP-1 antibodies. We conclude that DEP has only modest direct endothelial effects. In contrast, proinflammatory cytokines released from particle-laden MDMs appear to exacerbate endothelial activation after DEP exposure.
American Journal of Respiratory Cell and Molecular Biology 06/2011; 44(6):840-51. · 5.13 Impact Factor
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ABSTRACT: Mineralocorticoid receptor (MR) activation is proinflammatory and proatherogenic. Antagonism of MR improves survival in humans with congestive heart failure caused by atherosclerotic disease. In animal models, activation of MR exacerbates atherosclerosis. The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) prevents inappropriate activation of the MR by inactivating glucocorticoids in mineralocorticoid-target tissues. To determine whether glucocorticoid-mediated activation of MR increases atheromatous plaque formation, we generated Apoe(-/-)/11β-HSD2(-/-) double-knockout (E/b2) mice. On chow diet, E/b2 mice developed atherosclerotic lesions by 3 months of age, whereas Apolipoprotein E (Apoe(-/-)) mice remained lesion free. Brachiocephalic plaques in 3-month-old E/b2 mice showed increased macrophage and lipid content and reduced collagen content compared with similar sized brachiocephalic plaques in 6-month-old Apoe(-/-) mice. Crucially, treatment of E/b2 mice with eplerenone, an MR antagonist, reduced plaque development and macrophage infiltration while increasing collagen and smooth muscle cell content without any effect on systolic blood pressure. In contrast, reduction of systolic blood pressure in E/b2 mice using the epithelial sodium channel blocker amiloride produced a less-profound atheroprotective effect. Vascular cell adhesion molecule 1 expression was increased in the endothelium of E/b2 mice compared with Apoe(-/-) mice. Similarly, aldosterone increased vascular cell adhesion molecule 1 expression in mouse aortic endothelial cells, an effect mimicked by corticosterone only in the presence of an 11β-HSD2 inhibitor. Thus, loss of 11β-HSD2 leads to striking atherogenesis associated with activation of MR, stimulating proinflammatory processes in the endothelium of E/b2 mice.
Endocrinology 01/2011; 152(1):236-46. · 4.46 Impact Factor
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Nicholas M Morton,
Yvonne B Nelson,
Zoi Michailidou,
Emma M Di Rollo,
Lynne Ramage, Patrick W F Hadoke,
Jonathan R Seckl,
Lutz Bunger,
Simon Horvat,
Christopher J Kenyon,
Donald R Dunbar
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ABSTRACT: Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain.
To enrich for adipose tissue obesity genes a 'snap-shot' pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity.
A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity.
PLoS ONE 01/2011; 6(9):e23944. · 4.09 Impact Factor
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ABSTRACT: Traditional methods for the analysis of vascular lesion formation are labour intensive to perform - restricting study to 'snapshots' within each vessel. This study was undertaken to determine the suitability of optical projection tomographic (OPT) imaging for the 3-dimensional representation and quantification of intimal lesions in mouse arteries.
Vascular injury was induced by wire-insertion or ligation of the mouse femoral artery or administration of an atherogenic diet to apoE-deficient mice. Lesion formation was examined by OPT imaging of autofluorescent emission. Lesions could be clearly identified and distinguished from the underlying vascular wall. Planimetric measurements of lesion area correlated well with those made from histological sections subsequently produced from the same vessels (wire-injury: R² = 0.92; ligation-injury: R² = 0.89; atherosclerosis: R² = 0.85), confirming both the accuracy of this methodology and its non-destructive nature. It was also possible to record volumetric measurements of lesion and lumen and these were highly reproducible between scans (coefficient of variation = 5.36%, 11.39% and 4.79% for wire- and ligation-injury and atherosclerosis, respectively).
These data demonstrate the eminent suitability of OPT for imaging of atherosclerotic and neointimal lesion formation, providing a much needed means for the routine 3-dimensional analysis of vascular morphology in studies of this type.
PLoS ONE 01/2011; 6(2):e16906. · 4.09 Impact Factor
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Miriam E Gerlofs-Nijland,
Annike I Totlandsdal,
Evren Kilinç,
A John F Boere,
Paul H B Fokkens,
Daan L A C Leseman,
Constantinos Sioutas,
Per E Schwarze,
Henri M Spronk, Patrick W F Hadoke,
Mark R Miller,
Flemming R Cassee
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ABSTRACT: Traffic-related particulate matter (PM) may play an important role in the development of adverse health effects, as documented extensively in acute toxicity studies. However, rather little is known about the impacts of prolonged exposure to PM. We hypothesized that long-term exposure to PM from traffic adversely affects the pulmonary and cardiovascular system through exacerbation of an inflammatory response. To examine this hypothesis, Fisher F344 rats, with a mild pulmonary inflammation at the onset of exposure, were exposed for 4 weeks, 5 days/week for 6 h a day to: (a) diluted diesel engine exhaust (PM(DEE)), or: (b) near roadside PM (PM(2.5)). Ultrafine particulates, which are largely present in diesel soot, may enter the systemic circulation and directly or indirectly trigger cardiovascular effects. Hence, we assessed the effects of traffic-related PM on pulmonary inflammation and activity of procoagulants, vascular function in arteries, and cytokine levels in the heart 24 h after termination of the exposures. No major adverse health effects of prolonged exposure to traffic-related PM were detected. However, some systemic effects due to PM(DEE) exposure occurred including decreased numbers of white blood cells and reduced von Willebrand factor protein in the circulation. In addition, lung tissue factor activity is reduced in conjunction with reduced lung tissue thrombin generation. To what extent these alterations contribute to thrombotic effects and vascular diseases remains to be established. In conclusion, prolonged exposure to traffic-related PM in healthy animals may not be detrimental due to various biological adaptive response mechanisms.
Inhalation Toxicology 12/2010; 22(14):1162-73. · 1.92 Impact Factor
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Miriam E. Gerlofs-Nijland,
Annike I. Totlandsdal,
Evren Kilinç,
A. John F. Boere,
Paul H.B. Fokkens,
Daan L.A.C Leseman,
Constantinos Sioutas,
Per E. Schwarze,
Henri M. Spronk, Patrick W.F. Hadoke,
Mark R. Miller,
Flemming R. Cassee
[show abstract]
[hide abstract]
ABSTRACT: Traffic-related particulate matter (PM) may play an important role in the development of adverse health effects, as documented extensively in acute toxicity studies. However, rather little is known about the impacts of prolonged exposure to PM. We hypothesized that long-term exposure to PM from traffic adversely affects the pulmonary and cardiovascular system through exacerbation of an inflammatory response. To examine this hypothesis, Fisher F344 rats, with a mild pulmonary inflammation at the onset of exposure, were exposed for 4 weeks, 5 days/week for 6 h a day to: (a) diluted diesel engine exhaust (PMDEE), or: (b) near roadside PM (PM2.5). Ultrafine particulates, which are largely present in diesel soot, may enter the systemic circulation and directly or indirectly trigger cardiovascular effects. Hence, we assessed the effects of traffic-related PM on pulmonary inflammation and activity of procoagulants, vascular function in arteries, and cytokine levels in the heart 24 h after termination of the exposures. No major adverse health effects of prolonged exposure to traffic-related PM were detected. However, some systemic effects due to PMDEE exposure occurred including decreased numbers of white blood cells and reduced von Willebrand factor protein in the circulation. In addition, lung tissue factor activity is reduced in conjunction with reduced lung tissue thrombin generation. To what extent these alterations contribute to thrombotic effects and vascular diseases remains to be established. In conclusion, prolonged exposure to traffic-related PM in healthy animals may not be detrimental due to various biological adaptive response mechanisms.
Inhalation Toxicology 11/2010; 22(14):1162-1173. · 1.92 Impact Factor
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ABSTRACT: The vascular type of Ehlers-Danlos syndrome (EDS IV) is an autosomal-dominant disorder characterized by thin translucent skin and extensive bruising. Patients with EDS IV have reduced life expectancy (median 45-50 years) due to spontaneous rupture of arteries (particularly large arteries) or bowel. EDS IV results from mutation of the COL3A1 gene, which encodes the pro-α(1) chains of type III collagen that is secreted into the extracellular matrix, e.g. by smooth muscle cells. A mouse model of EDS IV produced by targeted ablation of Col3a1 has been of limited use as only 10% of homozygous animals survive to adulthood, whereas heterozygous animals do not die from arterial rupture. We report a novel, exploitable model of EDS IV in a spontaneously generated mouse line.
Mice were identified by predisposition to sudden, unexpected death from dissection of the thoracic aorta. Aortic dissection inheritance was autosomal-dominant, presented at an early age (median, 6 weeks) with incomplete penetrance, and had a similar sex ratio bias as EDS IV (2:1, male:female). Molecular genetic analysis demonstrated that the causal mutation is a spontaneous 185 kb deletion, including the promoter region and exons 1-39, of the Col3a1 gene. As in EDS IV, aortic dissection was not associated with elevated blood pressure, aneurysm formation, or infection, but may result from aberrant collagen fibrillogenesis within the aortic wall.
This novel, exploitable mouse line that faithfully models the vascular aspects of human EDS IV provides an important new tool for advancing understanding of EDS IV and of aortic dissection in general.
Cardiovascular research 11/2010; 90(1):182-90. · 5.80 Impact Factor
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Journal of hypertension 10/2010; 28(10):2170-1; author reply 2171. · 4.02 Impact Factor
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ABSTRACT: Recent studies suggest that kisspeptin (a neuropeptide central to the regulation of gonadotrophin secretion) has diverse roles in human physiology, including a putative role in implantation and placental function. Kisspeptin and its receptor are present in human blood vessels, where they mediate vasoconstriction, and kisspeptin is known to inhibit tumor metastasis and trophoblast invasion, both processes involving angiogenesis. We hypothesized that kisspeptin contributes to the regulation of angiogenesis in the reproductive system. The presence of the kisspeptin receptor was confirmed in human placental blood vessels and human umbilical vein endothelial cells (HUVEC) using immunochemistry. The ability of kisspeptin-10 (KP-10) (a shorter biologically active processed peptide) to inhibit angiogenesis was tested in explanted human placental arteries and HUVEC using complementary ex vivo and in vitro assays. KP-10 inhibited new vessel sprouting from placental arteries embedded in Matrigel and tube-like structure formation by HUVEC, in a concentration-dependent manner. KP-10 had no effect on HUVEC viability or apoptosis but induced concentration-dependent inhibition of proliferation and migration. In conclusion, KP-10 has antiangiogenic effects and, given its high expression in the placenta, may contribute to the regulation of angiogenesis in this tissue.
Endocrinology 10/2010; 151(12):5927-34. · 4.46 Impact Factor
