| 1. |
- Crisby, Milita
(author)
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Cell death in atherosclerosis
- 1998
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Doctoral thesis (other academic/artistic)abstract
- Rupture of atherosclerotic lesions is recognized as the major cause of acute cerebrovascular and coronary syndromes. The characteristics of the typical vulnerable plaque include increased inflammatory cells at the shoulder region, a large lipid core, a thin fibrous cap with few collagen fibers and smooth muscle cells. The release of proteolytic enzymes produced by macrophages, generation of cytokines by T cells and death of smooth muscle cells in lesions may contribute to plaque instability. Oxidation of LDL in the vessel wall renders the LDL particles proinflammatory and cytotxic. However, the type of cell death occurring in vivo and the factors responsible for its' induction have remained equivocal. Cholesterol homeostasis is achieved through regulation of the uptake, synthesis and esterification of cholesterol. It has been recently shown that extrahepatic cells such as macrophages can eliminate intracellular cholesterol by enzymatic conversion into 27-hydroxycholesterol and 3ß-hydroxy-5-cholestenoic acid. The sterol 27-hydroxylase is the enzyme responsible for the conversion of cholesterol to 27-oxygenated products. The introduction of statins, as potent inhibitors of HMG-CoA reductase has resulted in significant decrease in cardiovascular morbidity and mortality. Angiographic assessment has shown that improvement in arterial topographical morphology occurs slowly and only to a small extent (1-2%). These observations have led to the concept of plaque stabilisation, as a new strategy for prevention of acute cardiovascular syndromes. Advanced human carotid atherosclerotic plaques were characterized by a high frequency of degenerating smooth muscle cells with ongoing DNA fragmentation. The presence of DNA ladder suggested that some of these cells undergo apoptotic cell death, but electron microscopic analysis indicated that most dying cells in the plaque were in a state of oncosis. Analysis of the relation between DNA framentation and plaque cell composition demonstrated a significant association between degree of TUNEL positivity and T cell infiltration. High serum LDL cholesterol levels were associated with increased macrophage staining in atherosclerotic lesions. Degenerating cells were almost exclusively found in or very close to regions with strong oxidized LDL inummoreactivity. Exposure of smooth muscle cells to oxidized LDL induced cell death of a similar pattern found in atherosclerotic lesions. Sterol 27-hydroxylase functions as a defence towards accumulation of cholesterol in macrophages by enzymatic conversion of intracellular cholesterol into 27-hydroxycholesterol and 3ß-hydroxy-5-cholestenoic acid. We found the sterol 27-hydroxylase immunoreactivity to be located primarily to macrophages and endothelial cells in humans atherosclerotic lesions. In humans, the sterol 27-hydroxylase mechanism is more active compared to other species such as the rabbit. A substantially lower amount of lipids, particularly oxidized LDL, T cells and macrophages and degenerating cells were observed in atherosclerotic lesions obtained from patients with advanced carotid artery stenosis treated with pravastatin for 3 months prior to carotid endarterectomy. The present findings support the hypothesis that oxidized LDL is highly toxic towards vascular smooth muscle cells and induces oncosis, a pattern found in dying smooth muscle cells and other cells in advanced human carotid plaques. Moreover, they indicate that pravastatin treatment may stabilise the plaque composition by reducing oxidized LDL, inflammation and number of degenerating cell in vivo in humans.
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| 2. |
- Crisby, Milita, et al.
(author)
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Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques - Implications for plaque stabilization
- 2001
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In: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 1524-4539 .- 0009-7322. ; 103:7, s. 926-933
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Journal article (peer-reviewed)abstract
- Background--The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy. Methods and Results--Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid Plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2 +/-8.4% versus 23.9 +/- 21.1% of the plaque area, P<0.05), less oxidized LDL immunoreactivity (13.33.6% versus 22.0 +/-6.5%, P<0.001), fewer macrophages (15.010.2% versus 25.3 +/- 12.5%, P<0.05), fewer T cells (11.29.3% versus 24.3 +/- 13.4%, P<0.05), less matrix metalloproteinase 2 (MMP-2) immunoreactivity (3.63.9% versus 8.4 +/-5.3%, P<0.05), greater tissue inhibitor of metalloproteinase 1 (TIMP-1) immunoreactivity (9.06.2% versus 3.1 +/-3.9%, P<0.05), and a higher collagen content by Sirius red staining (12.43.1% versus 7.5 +/-3.5%, P<0.005), Cell death by TUNEL staining was reduced in the pravastatin group (17.77.8% versus 32.0 +/- 12.6%, P<0.05). Conclusions--Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.
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| 3. |
- Crisby, Milita, et al.
(author)
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Relation between Vascular Risk Factors and Carotid Plaque Cell Composition and Viability in Elderly Patients
- 2003
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In: Brain Ageing. - 1582-8352. ; 3:1, s. 38-42
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Journal article (peer-reviewed)abstract
- Objectives: Carotid stenosis is a crucial cause of ischemic stroke. Recent studies suggest that one of the most important effects of lipid-lowering statins is to stabilize vulnerable plaques. However, it remains to be determined if this effect is secondary to the lowering of plasma cholesterol levels or due to a direct effect of statins on plaques stability. Design and main outcome measures: In this study we have analyzed if plaque cell composition and the frequency of apoptotic DNA fragmentation are related to cholesterol levels or any of the major risk factors for vascular disease. The study group consisted of 49 patients undergoing carotid endarterectomy. The plaques were stained by immunohistochemical and TUNEL techniques and scored semi quantitatively by a blinded observer. Results: Rupture sites contained significantly more TUNEL-positive cells and T-cells, but less smooth muscle cells than intact areas of the fibrous cap. Plaques from hypercholesterolemic patients were found to have less TUNEL-positive cells, but otherwise hypercholesterolemia, low HDL cholesterol, hypertension, diabetes and smoking did not influence plaque cell composition or the frequency of TUNEL-positive cells. Conclusions: Our observations suggest that there are no associations between major vascular risk factors and plaque cell composition. Accordingly, they favor the notion that the effects of statins are due to a direct effect on plaque structure rather than solely secondary to lowering of plasma cholesterol.
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| 4. |
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| 5. |
- Poggesi, Anna, et al.
(author)
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Urinary complaints in nondisabled elderly people with age-related white matter changes: the Leukoaraiosis And DISability (LADIS) Study.
- 2008
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In: Journal of the American Geriatrics Society. - : Wiley. - 1532-5415 .- 0002-8614. ; 56:9, s. 1638-43
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To investigate, in a cohort of nondisabled elderly people, the association between urinary complaints and severity of age-related white matter changes (ARWMC). DESIGN: Cross-sectional data analysis from a longitudinal multinational study. SETTING: The Leukoaraiosis And DISability Study, assessing ARWMC as an independent predictor of the transition from functional autonomy to disability in elderly subjects. PARTICIPANTS: Six hundred thirty-nine subjects (288 men, 351 women, mean age 74.1+/-5.0) with magnetic resonance imaging (MRI)-detected ARWMC of different severity. MEASUREMENTS: ARWMC severity was graded on MRI as mild, moderate, and severe (Fazekas scale). MRI assessment also included ARWMC volumetric analysis and the count of infarcts. Urinary complaints (nocturia, urinary frequency, urgency, incontinence) were recorded based on subjects' answers to four questions. RESULTS: In comparing the three ARWMC severity groups, there was a significant difference only in prevalence of urgency, with 16% of subjects in the mild severity group, 17% in the moderate severity group, and 25% in the severe group (P=.03). Adjusting for age, sex, lacunar and nonlacunar infarcts, diabetes mellitus, and use of diuretics, severe ARWMC retained an independent effect in the association with urinary urgency (odds ratio=1.74, 95% confidence interval=1.04-2.90, severe vs mild group). Subjects with urinary urgency also had higher ARWMC volumes (25.2, vs 20.4 mm(3) in those without urinary urgency; P<.001). Urgency was confirmed to be associated with the severe degree of ARWMC, irrespective of complaints of memory, gait disturbances, or history of depression. CONCLUSION: In a cohort of nondisabled elderly people, severe ARWMC were associated with urinary urgency, independent of other potential confounders and vascular lesions of the brain.
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| 6. |
- Sun, Yongxin, et al.
(author)
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Pravastatin inhibits pro-inflammatory effects of Alzheimer's peptide Abeta(1-42) in glioma cell culture in vitro.
- 2003
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In: Pharmacological Research. - 1096-1186 .- 1043-6618. ; 47:2, s. 119-126
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Journal article (peer-reviewed)abstract
- Statins are known to exert a number of biological effects apart from reducing cholesterol synthesis. The results of recent studies indicate that patients treated with pravastatin have a lower prevalence of diagnosed Alzheimer’s disease (AD). These observations prompted us to examine the effects of pravastatin on Alzheimer’s peptide (Aβ1–42)-induced pro-inflammatory activation in the human glioma cell line in vitro. Cells alone or cells pre-treated with pravastatin (0.1 mg ml−1) for 24 h were stimulated with 5 μM of freshly dissolved Aβ1–42 for the next 24 h. The pre-treatment of cells with pravastatin diminished the capacity of Aβ to induce metalloproteinases, cytokine IL-6 and free radical levels. Although both pravastatin and Aβ1–42 separately increased PPARγ activity, the combination of Aβ1–42 and pravastatin resulted in no effect on PPARγ expression. These data indicate that soluble forms of Aβ1–42, which are a potent stimulus of pro-inflammatory activation of glioma cells in vitro, could be a good target for pravastatin.
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| 7. |
- Wanby, Pär
(author)
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On certain genetic and metabolic risk factors for carotid stenosis and stroke
- 2006
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Doctoral thesis (other academic/artistic)abstract
- The present study evaluated genetic and metabolic factors influencing the risk of acute cerebrovascular disease (CVD) and internal carotid artery stenosis (ICA stenosis) in a Swedish community. The threonine (T) containing protein of the FABP2 A54T gene polymorphism has a greater affinity for long chain fatty acids (FFAs) than the alanine (A) containing protein. This altered affinity for FFAs has been shown to affect the intestinal absorption of fatty acids and consequently the fatty acid composition of serum lipids, in particularly postprandially. Endothelium derived NO is a potent vasodilator and antiatherogenic agent. Asymmetric dimethyl arginine (ADMA) is an endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS). ADMA has been shown to be involved in the pathogenesis of atherosclerotic disease, and ADMA inhibits eNOS by displacement of L-arginine from the enzyme, which in turn is believed to affect the amount of NO available within the endothelium.The FABP2 A54T gene polymorphism was analyzed in 407 patients with acute CVD and also in a subset of these patients whose carotids had been evaluated with ultrasound. Both the FABP2 polymorphism and a common polymorphism of the eNOS gene, Glu298Asp, were analyzed in a different population consisting of 54 matched pairs of patients with ICA stenosis and controls. ADMA levels were measured in both study populations.We found that the T54 allele was more frequent in patients with transient ischaemic attacks (TIA), and that the TT genotype was more prevalent in young, non-smoking patients with CVD than in controls.Increased concentrations of ADMA were observed in cardio-embolic infarction and TIA, but not significantly in non-cardio-embolic infarction nor in haemorrhagic stroke. In multivariate logistic regression models, CVD increased across quartiles of ADMA in all subgroups, but this association was only significant in the TIA group. A decreased arginine/ADMA ratio, a measure of NO availability was associated with CVD in the entire study population. Patients with severe carotid stenosis had significantly higher ADMA levels than the controls. Allele and genotype frequencies of the FABP2 and eNOS polymorphisms did not differ between patients with ICA stenosis and controls.Our results indicate that ADMA is a strong marker for TIA and severe ICA stenosis, and that relative defiency of arginine, measured as L-arginine/ADMA, is present in acute CVD.We also conclude that a common polymorphism of the FABP2 gene increases susceptibility to ischaemic stroke and TIA.
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| 8. |
- Zelvyté, Inga, et al.
(author)
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Modulation of inflammatory mediators and ppargammaand nfkappab expression by pravastatin in response to lipoproteins in human monocytes in vitro.
- 2002
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In: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 45:2, s. 147-154
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Journal article (peer-reviewed)abstract
- Statins are inhibitors of the rate-limiting step of cellular cholesterol synthesis. In vitro and in vivo studies suggest that statins have anti-inflammatory properties independent of their cholesterol-lowering effects. These observations prompted us to examine the effects of pravastatin (50 mgr; M) and native or oxidized low density lipoprotein (nLDL or oxLDL) (50 mgr; g ml(minus sign1)) on primary human monocytes. We found that cells treated with pravastatin prior to nLDL and cells pre-treated with oxLDL prior to pravastatin showed increased activity of peroxisome proliferator-activated receptor gamma (PPAR gamma). Treatment of cells with drug either before incubation with oxLDL or afterwards suppressed nuclear factor kappa B (NF kappa B) expression and reduced uptake of(125)I-oxLDL by 1.7- and 1.5-fold, respectively. Pravastatin also increased PPAR gamma levels and abolished NF kappa B activity in non-stimulated monocytes. Statin added to monocytes prior to or after treatment with nLDL or oxLDL significantly inhibited generation of matrix metalloproteinases (MMPs), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF- alpha). These data corroborate previous findings of the pleiotropic role of statins and also suggest the involvement of transcription factors such as PPAR gamma and NF kappa B in the modulation of the inflammatory processes by statins. Copyright 2002 Elsevier Science Ltd.
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