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Biomedical subjects

Jan Nilsson

Publications and source records attributed to Jan Nilsson.

47 records · Page 3Linked to original sources
PubMed2003

Changes related to age and cerebrovascular symptoms in the extracellular matrix of human carotid plaques.

BACKGROUND AND PURPOSE: Many processes involved in the pathogenesis of atherosclerosis result in modifications of the extracellular matrix. These changes not only determine the mechanical stability of atherosclerotic lesions but can directly or indirectly influence further development of the lesions. The purpose of the present study was to compare the matrix composition of human carotid plaques from symptomatic patients with those obtained from patients without symptoms. Furthermore, matrix changes related to age were studied. METHODS: Thirty atherosclerotic carotid plaques were removed by endarterectomy from 27 patients and divided into 2 groups on the basis of the presence of ipsilateral symptoms. The plaques were homogenized, and the total levels of the major components of the extracellular matrix were determined. RESULTS: Plaques associated with symptoms were characterized by increased levels of elastin (1.58+/-0.46 versus 1.24+/-0.40 mg/g wet wt; P=0.03) and decreased levels of hydroxyapatite (45.1+/-46.3 versus 131.4+/-111.7 mg/g wet wt; P=0.02) compared with asymptomatic plaques. The increase in elastin in plaques from symptomatic patients was due to elevated levels of an intermediate-size fraction, as determined by liquid chromatography. Collagen and sulfated glycosaminoglycans were present in equal amounts in both groups. Elastin content in carotid plaques decreased with age. CONCLUSIONS: Carotid plaques from symptomatic patients have lower levels of hydroxyapatite than those from asymptomatic patients. The present study also raises the possibility that non-cross-linked forms of elastin, increased in plaques associated with symptoms, could be a marker of plaque vulnerability and/or directly induce harmful cellular activities or increase lipoprotein retention in the vascular wall.

Age Factors↗
PubMed2003

HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells.

OBJECTIVE: Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. METHODS AND RESULTS: Simvastatin, atorvastatin, and lovastatin (0.1 to 10 micro mol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-kappaB or AP-1-dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated IkappaB-alpha protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1alpha. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells. CONCLUSIONS: HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-kappaB, AP-1, and hypoxia-inducible factor-1alpha. These findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases.

Atorvastatin↗
PubMed2003

Autoantibodies against modified low-density lipoproteins in coronary artery disease.

OBJECTIVES: To evaluate the importance of different autoantibodies against modified low-density lipoprotein (LDL) in patients with coronary artery disease (CAD). BACKGROUND: Previous studies of autoantibodies against LDL have shown that patients with CAD have increased titers of autoantibodies against LDL modified by copper and malondialdehyde (MDA), whereas there is a lack of information about autoantibody titers against LDL modified by hypochlorite (HOCl). Studies of autoantibodies in relation to severity of atherosclerosis are few and have reached divergent results. Furthermore, no data exist on the relationship between autoantibody titers and prognosis. METHODS: Titers of autoantibodies against copper-, MDA- and HOCl-modified LDL were determined in serum by ELISA. Autoantibody titers in young male survivors of a first myocardial infarction were compared with those of healthy controls and related to coronary angiographic findings and to prognosis during 11 years of follow-up. RESULTS: Patients had higher titers of autoantibodies against LDL modified by copper and MDA than controls. In contrast, no consistent associations were found between autoantibody titers and global severity of coronary atherosclerosis or number and severity of coronary stenoses and prognosis. CONCLUSIONS: The prognostic value of autoantibodies against modified LDL is limited in young postinfarction patients despite the fact that autoantibody titers against copper- and MDA-modified LDL are raised compared with healthy controls. Furthermore, the results indicate that autoantibodies against modified LDL are not protective in later stages of coronary atherosclerosis.

Adult↗
PubMed2003

Can continuous physical training counteract aging effect on myoelectric fatigue? A surface electromyography study application.

OBJECTIVES: To compare the myoelectric onset of muscle fatigue in physically active trained young skiers with respect to elderly skiers and to test whether continuous training can counteract the selective loss of type II muscle fibers usually observed with aging. DESIGN: An observational, cross-sectional study of the myoelectric onset of muscle fatigue in the left tibialis anterior muscles. SETTING: Surface electromyography recorded with portable devices at a downhill ski rescue lodge in the Italian Alps. PARTICIPANTS: Fifty-four physically trained, active skiers (43 men, 11 women; age range, 24-85y). INTERVENTIONS: Questionnaire on physical activity and 2 sustained isometric voluntary contractions at 20% and 2 at 80% of the maximal voluntary contraction level. MAIN OUTCOME MEASURES: Isometric contractions and mean and median spectral frequencies calculated to monitor the myoelectric manifestations of muscle fatigue. RESULTS: Fatigue indices did not differ significantly between younger and older subjects and, thus, did not show a correlation between myoelectric manifestations of muscle fatigue and age in physically active subjects. CONCLUSION: It appears possible that aging skeletal muscles subjected to continuous exercise develop an adaptive response that counteracts the selective loss of type II muscle fibers usually observed in the muscles of elderly sedentary subjects. Our results suggest that physical activity could be considered in the elderly within a broad rehabilitative framework in which appropriate and even tailored physical training could be planned to counteract the physiologic effects of aging on muscle fiber distribution.

Adult↗
PubMed2003

Insulin-like growth factor II and its receptors in atherosclerosis and in conditions predisposing to atherosclerosis.

PURPOSE OF REVIEW: Growth factors regulate cellular migration, proliferation, and the production of extracellular matrix during the development of the atherosclerotic lesion. Here we discuss experimental evidence pointing to insulin-like growth factor II and its receptors as important players in cardiovascular diseases. RECENT FINDINGS: Genetically modified mice with altered levels of insulin-like growth factor II or receptors mediating insulin-like growth factor II signalling showed abnormalities known to be associated with, or contribute to, ageing and atherosclerosis in humans. These animal models displayed abnormalities in the morphology of the aortic tissue, glucose tolerance, response to oxidative stress and life span. Furthermore, human population studies showed a significant association between polymorphisms in the insulin-like growth factor II gene and obesity, a major risk factor for atherosclerosis. SUMMARY: Direct and indirect evidence in animal models points to insulin-like growth factor II and its signalling receptors as crucial players in atherosclerosis and in the onset of conditions predisposing to the disease. Furthermore, human population studies have established significant associations between specific polymorphisms at the insulin-like growth factor II gene and obesity which is an important risk factor for atherosclerosis. Future investigations should aim at understanding the molecular mechanisms underlying these effects and elucidating the potential role of the type 2 insulin-like growth factor receptor in the development of atherosclerotic lesions.

Animals↗
PubMed2003

Shortened life span, bradycardia, and hypotension in mice with targeted expression of an Igf2 transgene in smooth muscle cells.

IGF2 is known to affect the normal development and pathology of the cardiovascular system. We previously created mutant mice with targeted expression of an Igf2 transgene in the smooth muscle cells and showed that these mice spontaneously develop aortic intimal cushions. In the present work, we provide a general description of the phenotype of two independent lines of heterozygous transgenics. These mice showed organomegaly and a shortened life span. The latter trait was stronger in the line with a relatively more marked organomegaly and more pronounced in males than females in both lines. Postmortem histology revealed gross abnormalities of the cardiac architecture, suggesting that transgenic mice may accumulate lethal cardiovascular defects. Accordingly, apparently normal transgenic mice had mild cardiomegaly, an enlarged left ventricle, bradycardia, and hypotension. These observations are discussed in the light of the proposed therapeutic use of IGF2 in human cardiac diseases.

Animals↗
PubMed2002

Decreased inducibility of TNF expression in lipid-loaded macrophages.

BACKGROUND: Inflammation and immune responses are considered to be very important in the pathogenesis of atherosclerosis. Lipid accumulation in macrophages of the arterial intima is a characteristic feature of atherosclerosis which can influence the inflammatory potential of macrophages. We studied the effects of lipid loading on the regulation of TNF expression in human monocyte-derived macrophages. RESULTS: In macrophages incubated with acetylated low density lipoprotein (ac-LDL) for 2 days, mRNA expression of TNF in cells stimulated with TNF decreased by 75%. In cell cultures stimulated over night with IL-1beta, lipid loading decreased secretion of TNF into culture medium by 48%. These results suggest that lipid accumulation in macrophages makes them less responsive to inflammatory stimuli. Decreased basal activity and inducibility of transcription factor AP-1 was observed in lipid-loaded cells, suggesting a mechanism for the suppression of cytokine expression. NF-kappaB binding activity and inducibility were only marginally affected by ac-LDL. LDL and ac-LDL did not activate PPARgamma. In contrast, oxidized LDL stimulated AP-1 and PPARgamma but inhibited NF-kappaB, indicating that the effects of lipid loading with ac-LDL were not due to oxidation of lipids. CONCLUSIONS: Accumulation of lipid, mainly cholesterol, results in down-regulation of TNF expression in macrophages. Since monocytes are known to be activated by cell adhesion, these results suggest that foam cells in atherosclerotic plaques may contribute less potently to an inflammatory reaction than newly arrived monocytes/macrophages.

Cell Separation↗
PubMed2002

Inhibitory effect on arterial injury-induced neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice.

We investigated the effect of B-cell reconstitution in immune-deficient Rag-1 knockout (KO) mice subjected to arterial injury. After 21 days, injury induced a 4- to 5-fold increase in neointimal formation in Rag-1 KO mice fed normal chow compared with wild-type (WT) mice (0.020+/-0.0160 [n=8] versus 0.0049+/-0.0022 [n=8] mm(2), respectively; P<0.05) and in western-type diet-fed Rag-1 KO mice compared with WT mice (0.0312+/-0.0174 [n=7] versus 0.0050+/-0.0028 [n=6] mm(2), respectively; P<0.05). To investigate the role of B cells in response to injury, Rag-1 KO mice were reconstituted with B cells derived from the spleens of WT mice, with donors and recipients on the same diet. Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed normal chow) reduced neointimal formation compared with the effect in unreconstituted Rag-1 KO mice (0.0076+/-0.0039 [n=9] versus 0.020+/-0.0160 [n=8] mm(2), respectively; P<0.05). Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed a western diet) reduced neointimal formation compared the effect in Rag-1 KO mice (0.0087+/-0.0037 [n=8] versus 0.0312+/-0.0174 [n=7] mm(2), respectively; P<0.05). Injured carotid arteries from reconstituted Rag-1 KO mice had detectable IgM and IgG, indicating viable transfer of B cells. The results suggest that B cells modulate the response to arterial injury.

Adoptive Transfer↗
PubMed2002

Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factor-kappaB activation.

Endothelial activation is an important step in atherogenesis. In addition to established cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, and homocysteinemia, high plasma levels of triglyceride-rich lipoproteins may be an important cause of endothelial activation as well. Free fatty acids hydrolyzed from core triglycerides of these particles can exert both pro- and anti-inflammatory effects on the vascular wall. omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to inhibit cytokine-induced endothelial activation. In contrast, we and others have previously shown that the omega-6 fatty acid linoleate activates transcription factor nuclear factor-kappaB (NF-kappaB) in endothelial cells. In this study, we show that linoleic acid stimulates vascular adhesion molecule-1 (VCAM-1) protein and mRNA expression in cultured human endothelial cells, as assessed by immunofluorescence and Northern blotting. Release of shedded soluble VCAM-1 from cultured human endothelial cells was also increased by the addition of linoleic acid, as determined by enzyme-linked immunosorbent assay (ELISA). By use of cultured rat aortic endothelial cells transfected with an IkappaB super-repressor (DeltaN2 cells), we provide evidence that NF-kappaB signalling is required in the linoleic acid-induced VCAM-1 expression in endothelial cells, whereas other transcription factors appear to be involved in the increased endothelial plasminogen activator inhibitor-1 (PAI-1) production in response to linoleic acid. These findings suggest that diets rich in linoleic acid may be proinflammatory and thus atherogenic by activating vascular endothelial cells.

Animals↗
PubMed2001

Insulin-like growth factor II plays a central role in atherosclerosis in a mouse model.

Insulin-like growth factor II is a fetal promoter of cell proliferation that is involved in some forms of cancer and overgrowth syndromes in humans. Here, we provide two sources of genetic evidence for a novel, pivotal role of locally produced insulin-like growth factor II in the development of atherosclerosis. First, we show that homozygosity for a disrupted insulin-like growth factor II allele in mice lacking apolipoprotein E, a widely used animal model of atherosclerosis, results in aortic lesions that are approximately 80% smaller and contain approximately 50% less proliferating cells compared with mice lacking only apolipoprotein E. Second, targeted expression of an insulin-like growth factor II transgene in smooth muscle cells, but not the mere elevation of circulating levels of the peptide, causes per se aortic focal intimal thickenings. The insulin-like growth factor II transgenics presented here are the first viable mutant mice spontaneously developing intimal masses. These observations provide the first direct evidence for an atherogenic activity of insulin-like growth factor II in vivo.

Animals↗