29 results on '"Levula, Mari"'
Search Results
2. A genome-wide expression quantitative trait loci analysis of proprotein convertase subtilisin/kexin enzymes identifies a novel regulatory gene variant for FURIN expression and blood pressure
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Turpeinen, Hannu, Seppälä, Ilkka, Lyytikäinen, Leo-Pekka, Raitoharju, Emma, Hutri-Kähönen, Nina, Levula, Mari, Oksala, Niku, Waldenberger, Melanie, Klopp, Norman, Illig, Thomas, Mononen, Nina, Laaksonen, Reijo, Raitakari, Olli, Kähönen, Mika, Lehtimäki, Terho, and Pesu, Marko
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- 2015
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3. Apoptosis-related molecules in blood in multiple sclerosis
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Rinta, Sanna, Kuusisto, Hanna, Raunio, Minna, Paalavuo, Raija, Levula, Mari, Lehtimäki, Terho, and Elovaara, Irina
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- 2008
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4. Interleukin 18 gene promoter polymorphism: a link between hypertension and pre-hospital sudden cardiac death: the Helsinki Sudden Death Study
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Hernesniemi, Jussi A., Karhunen, Pekka J., Oksala, Niku, Kähönen, Mika, Levula, Mari, Rontu, Riikka, Ilveskoski, Erkki, Kajander, Olli, Goebeler, Sirkka, Viiri, Leena E., Hurme, Mikko, and Lehtimäki, Terho
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- 2009
5. Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death
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Kytömäki Leena, Salenius Juha-Pekka, Vihinen Mauno, Thusberg Janita, Oksala Niku, Järvinen Otso, Kajander Olli A, Ilveskoski Erkki, Mikkelsson Jussi, Karhunen Pekka J, Levula Mari, Fan Yue-Mei, Soini Juhani T, Laaksonen Reijo, and Lehtimäki Terho
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Background Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, SREBF-2 1784G>C (rs2228314) and SCAP 2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD). Methods Whole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33–69 years) Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the SREBF-2 and SCAP genotypes. Results Whole genome expression profiling showed a significant (p = 0.02) down-regulation of SREBF-2 in atherosclerotic carotid plaques (types IV-V), but not in the aorta or femoral arteries (p = NS for both), as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the SREBF-2 1784G>C and the SCAP 2386A>G genotype was observed on the risk of SCD (p = 0.046). Men with the SREBF-2 C allele and the SCAP G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07–6.71), compared to SCAP AA homologous subjects carrying the SREBF-2 C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the results were not statistically significant. Conclusion The results suggest that the allelic variants (SREBF-2 1784G>C and SCAP 2386A>G) in the cholesterol homeostasis regulating SREBF-SCAP pathway may contribute to SCD in early middle-aged men.
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- 2008
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6. Gene expression profiles in Finnish twins with multiple sclerosis
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Kaprio Jaakko, Lehtimäki Terho, Airla Nina, Levula Mari, Paalavuo Raija, Kuusisto Hanna, Särkijärvi Silja, Koskenvuo Markku, and Elovaara Irina
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Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Since genetic alterations influencing susceptibility to multiple sclerosis (MS), the most common autoimmune demyelinating disease of the central nervous system (CNS), are as yet poorly understood, the purpose of this study was to identify genes responsible for MS by studying monozygotic (MZ) twin pairs discordant for MS. Methods In order to identify genes involved in MS development, the gene expression profiles in blood mononuclear cells obtained from eight MZ twin pairs discordant for MS were analyzed by cDNA microarray technology detecting the expression of 8 300 genes. The twins were collected from the Finnish Twin Cohort Study and both affected subjects and their healthy siblings underwent neurological evaluation and cerebral and spinal magnetic resonance imaging. Gene expressions were confirmed by relative quantitative reverse transcription PCR. Results It appeared that 25 genes were at least two-fold up-regulated and 15 genes down-regulated in 25% (2/8) of twins with MS when compared to their healthy siblings. Moreover, 6/25 genes were up-regulated in 40% of MS twins and one gene, interferon alpha-inducible protein (clone IFI-6-16) (G1P3), in 50% of them. The six most constantly expressed genes are (1) G1P3, (2) POU domain, class 3, transcription factor 1, (3) myxovirus resistance 2, (4) lysosomal-associated multispanning membrane protein-5, (5) hemoglobin alpha 2 and (6) hemoglobin beta. Conclusion Over two-fold up-regulation of these six genes in almost half of MZ twins with MS suggests their role in MS pathogenesis. Studies using MZ MS twins obtained from genetically homogeneous population offer a unique opportunity to explore the genetic nature of MS.
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- 2006
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7. Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque
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Fan, Yue-Mei, Hernesniemi, Jussi, Oksala, Niku, Levula, Mari, Raitoharju, Emma, Collings, Auni, Lyytikäinen, Leo-Pekka, Seppälä, Ilkka, Salenius, Juha-Pekka, Laaksonen, Reijo, Kähönen, Mika, Hutri-Kähönen, Nina, Lehtimäki, Terho, Lääketieteen yksikkö - School of Medicine, and University of Tampere
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Biolääketieteet - Biomedicine - Abstract
Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.
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- 2014
8. Genes involved in systemic and arterial bed dependent atherosclerosis - Tampere Vascular Study
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Levula, Mari, Oksala, Niku, Airla, Nina, Laaksonen, Reijo, Kähönen, Mika, Pelto-Huikko, Markku, Lehtimäki, Terho, Lääketieteen yksikkö - School of Medicine, and University of Tampere
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Biolääketieteet - Biomedicine - Abstract
Background Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed. Methodology/Principal Findings We characterized the genes generally involved in human advanced atherosclerotic (AHA type V–VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value
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- 2012
9. Gene expression profiling of human lipoprotein-loaded macrophages and atherosclerotic lesions with special emphasis on ADAMs
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Levula, Mari, Lääketieteen laitos - Medical School, Lääketieteellinen tiedekunta - Faculty of Medicine, and University of Tampere
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geeni ,ateroskleroosi ,tulehdus ,inflammation ,Kliininen kemia - Clinical Chemistry ,gene expression ,mikroarray ,atherosclerosis ,microarray ,LDL - Abstract
Ateroskleroosi on monitekijäinen sairaus, jonka kehittymiseen vaikuttavat perimä ja ympäristötekijät. Sairaus aiheuttaa vuosikymmenien saatossa valtimoiden tukkeutumista, mikä johtaa verenkiertohäiriöihin sydämessä, aivoissa ja alaraajoissa. Koska plasman korkea LDL- (low-density lipoprotein) kolesterolipitoisuus on ateroskleroosin huomattavimpia riskitekijöitä, on ateroskleroosin uskottu johtuvan pääasiallisesti rasva-aineiden kerääntymisestä verisuonen seinämään. Nykykäsityksen mukaan ateroskleroosia voidaan kuitenkin tarkastella kroonisena tulehdussairautena, jonka etenemisessä etenkin hapettuneilla lipoproteiineilla, monosyyteistä erilaistuneilla makrofageilla ja T-soluilla on merkittävä rooli. Ateroskleroosin syntymiseen ja etenemiseen vaikuttavia tekijöitä voidaan tutkia selvittämällä sairaudessa ilmentyviä geenejä tai usean geenin muodostamia aineenvaihduntateitä. Tässä väitöskirjatyössä pyrittiin löytämään geenejä, jotka vaikuttavat ateroskleroosin syntymiseen ja kehittymiseen. Tutkimuksessa pyrittiin selvittämään ateroskleroosin alkuvaiheen verisuonimuutoksiin liittyviä geenejä tutkimalla ihmisen monosyytti-makrofagien geenien ilmentymisen muuttumista altistettaessa niitä normaaleille ja hapettuneille LDL- ja HDL- (high-density lipoprotein) hiukkasille. Tutkimuksessa havaittiin hapettuneiden LDL- ja HDL-hiukkasten vaikutuksen olevan pääasiallisesti vastakkainen monosyytti-makrofagien geenien ilmentymiseen, vaikkakin huomattava osa geeneistä ilmentyi samansuuntaisesti lipoproteiinikäsittelyiden jälkeen. Elimistössä myös HDL-hiukkaset ovat alttiita hapettumiselle, joten tutkimuksen perusteella myös hapettuneet HDL-hiukkaset voivat myötävaikuttaa ateroskleroosin kehittymiseen. Tutkimuksessa havaittiin useita uusia ateroskleroosin varhaisvaiheisiin mahdollisesti liittyviä geenejä, joita ei oltu aikaisemmin liitetty ateroskleroosiin. Soluviljelykokeiden lisäksi tutkimuksessa kartoitettiin ihmisten kaikkien geenien ilmentyminen ateroskleroottisissa kaula-, reisi- ja aortta-valtimoissa sekä terveissä rintakehän seinämävaltimoissa ja pyrittiin löytämään geenejä, jotka osallistuvat pidemmälle edenneen ateroskleroottisen vaurion kehittymiseen. Tutkimuksessa selvitettiin ateroskleroottisissa valtimoissa eniten ja vähiten ilmentyvät yksittäiset geenit, sairaudessa muuntuneet geenien toiminnalliset kokonaisuudet ja aineenvaihduntatiet, sekä karakterisoitiin kullekin ateroskleroottisille valtimoille ominaiset geenien ilmentymisen muutokset. Koko perimän laajuisia geenien ilmentymisen tutkimuksia on tehty aikaisemminkin, mutta tässä tutkimuksessa selvitettiin ensimmäistä kertaa kolmessa ateroskleroottisessa valtimossa ilmentyvät geenit sekä kuvattiin yksittäisiä geenejä, jotka ovat aktiivisena ainoastaan tietyn valtimon ateroskleroosissa. Koska ateroskleroosi on sairaus, johon osallistuu kymmeniä, ellei satoja geenejä, auttavat tutkimuksessa selvitetyt ateroskleoottisissa valtimoissa muuntuneet aineenvaihduntatiet ymmärtämään kokonaisvaltaisesti ateroskleroosin kehittymistä. Tutkimuksessa havaittiin myös yksittäisiä geenejä, joiden ilmentymisen havaittiin muuttuneen ainoastaan ateroskleroottisessa aortta- tai reisivaltimossa. Tälläisten kullekin ateroskleroottiselle valtimolle ominaisten geenien selvittäminen auttaa ymmärtämään näihin valtimoihin kehittyvän sairauden erityispiirteitä. Tutkittaessa kaikkien ihmisten geenien ilmentymistä ateroskleroottisissa valtimoissa, havaittiin ADAM- (A Disintegrin And Metalloprotease) metalloproteaasien ilmentymisen muuttuneen sairaissa valtimoissa verrattuna terveisiin valtimoihin. Tutkimuksessa havaittiin ADAM8, -9, -15 ja -17 mRNA:n ja proteiinien määrän lisääntyneen ateroskleroottisissa vaurioissa ja ADAM8 geenivariaation liittyvän komplisoituneiden ateroskleroottisten vaurioiden pinta-alaan ja sydänäkkikuolemaan. ADAM-metalloproteaasien yhteyttä ateroskleroosin on tutkittu maailmalla vähän ja tulos ADAM8:n yhteydestä ateroskleroosin on uusi. Koska ADAM-metalloproteaaseilla on useita ateroskleroosin kannalta mielenkiintoisia ominaisuuksia, esimerkiksi sytokiinien ja kasvutekijöiden aktivointi tai inaktivointi, voi lisääntynyt ADAM-metalloproteaasien ilmentyminen ateroskleroosissa vaikuttaa huomattavasti sairaudelle tyypillisen tulehdusprosessin etenemiseen. Atherosclerosis is the most important cause of cardiovascular diseases and globally, the major cause of death. Generally, atherosclerosis can be considered to be a form of chronic inflammation resulting from interaction between modified lipoproteins, monocyte-derived macrophages, T cells, and the normal cellular elements of the arterial wall. The objectives of the thesis were to 1) study the gene expression changes induced by oxidized low-density lipoprotein (ox-LDL) and oxidized high-density lipoprotein (ox-HDL) molecules in cultured human monocyte-macrophages, 2) study the gene expression changes that prevail in advanced human atherosclerotic arteries, 3) define the expression of ADAM8 mRNA and protein in atherosclerotic arteries and study if there is an association of its 2662 T/G allelic variant (rs2995300) with atherosclerosis and myocardial infarction (MI) and 4) define the expression of ADAM9, -15 and -17 mRNA and protein in human atherosclerotic plaques and identify their catalytically active forms in the plaques. The gene expression changes characterizing early atherosclerotic lesion formation were studied with cDNA microarray and quantitative RT-PCR (QRT-PCR) using cultured human monocyte-macrophages obtained from leukocyte-rich buffy coats collected from healthy blood donors. The Tampere Vascular Study (TVS) material was used to evaluate the gene expression changes prevailing in advanced human atherosclerotic arteries using genome-wide oligonucleotide array. The TVS study material consisted altogether of 24 atherosclerotic arteries and six non atherosclerotic control arteries. Atherosclerotic arteries were collected from carotid and femoral arteries as well as abdominal aortas. Internal thoracic arteries were used as controls. Gene expression changes were verified with QRT-PCR and the localization of the ADAM proteins studied was studied with immunohistochemistry. The association of ADAM8 allelic variant with atherosclerosis and MI was analyzed with TaqMan 5´exonuclease assay and fluorescent allele-specific TagMan probes using the Helsinki Sudden Death Study (HSDS) material. 1) Ox-LDL and ox-HDL significantly affected the gene expression profiles of monocyte-macrophages. Lipoprotein treatments (LDL vs. HDL) mainly induced opposite expression in the gene expression of monocyte-macrophages but in addition, a significant number of genes was found to respond similarly to lipoprotein treatments. Several new candidate genes for foam cell formation were found. 2) Using genome-wide gene expression array (GWEA), we characterized the generally most up- and down-regulated genes in atherosclerotic plaques and found eight genes specific for aortic plaques and three genes for femoral plaques. In addition, a total of 28 pathways dysregulated (20 up- and 8 down-regulated compared to non-atherosclerotic controls) in plaques were defined with special emphasis on a T cell chemokine pathway. 3-4) The expression of ADAM8, -9, -15 and -17 were found to be significantly induced in the atherosclerotic plaques and the allelic variant of ADAM8 (rs2995300) was significantly associated with the area of complicated atherosclerotic plaques and fatal MI in HSDS material. Microarray technology was found to be applicable in the screening of gene expression changes in lipoprotein-loaded monocyte-macrophages as well as in advanced human atherosclerotic arteries. Several novel candidate genes and pathways potentially involved in the development of atherosclerosis were found. The pronounced expression of ADAM8, -9, -15, and -17 in the atherosclerotic plaque and the association of ADAM8 allelic variant with the areas of complicated atherosclerotic plaques and fatal myocardial infarct support the involvement of ADAMs in atherosclerosis.
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- 2009
10. Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque.
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Yue-Mei Fan, Hernesniemi, Jussi, Oksala, Niku, Levula, Mari, Raitoharju, Emma, Collings, Auni, Hutri-Kähönen, Nina, Juonala, Markus, Marniemi, Jukka, Lyytikäinen, Leo-Pekka, Seppälä, Ilkka, Mennander, Ari, Tarkka, Matti, Kangas, Antti J., Soininen, Pasi, Salenius, Juha Pekka, Klopp, Norman, Illig, Thomas, Laitinen, Tomi, and Ala-Korpela, Mika
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TRANSCRIPTION factors ,LIPOPROTEINS ,METABOLISM ,ATHEROSCLEROTIC plaque ,ATHEROSCLEROSIS ,LIPIDS ,MESSENGER RNA - Abstract
Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT
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- 2014
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11. Association of Neuroimmune Guidance Cue Netrin-1 and Its Chemorepulsive Receptor UNC5B With Atherosclerotic Plaque Expression Signatures and Stability in Human(s).
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Oksala, Niku, Pärssinen, Jenita, Seppälä, Ilkka, Raitoharju, Emma, Ivana, Kholova, Hernesniemi, Jussi, Lyytikäinen, Leo-Pekka, Levula, Mari, Mäkelä, Kari-Matti, Sioris, Thanos, Kähönen, Mika, Laaksonen, Reijo, Hytönen, Vesa, and Lehtimäki, Terho
- Abstract
Macrophage (MΦ) infiltration and smooth muscle cell (SMC) proliferation are hallmarks of atherosclerosis and unstable plaques. Neuroimmune guidance cue 1 (netrin-1 [NTN1]) plays a critical role controlling MΦ trafficking and SMC activation. Characterization of expression of NTN1 and its receptors and their association with plaque stability in human(s) is lacking.The expression of NTN1 and its receptors did not differ in either whole blood or circulating monocytes from patients with coronary artery disease (n=55) compared with healthy controls (n=45). However, NTN1 was downregulated (-2.9-fold; P<0.0001) and UNC5B upregulated (2.2-fold; P<0.0001) in atherosclerotic plaques (n=68), whereas there were no differences in other NTN1 receptors compared with histologically normal controls (n=28). Increased UNC5B expression is associated with histologically more stable plaques (P=0.011). NTN1 expression correlated positively with SMC markers and signatures and negatively with inflammatory markers and M1 and especially M2 signatures in the atherosclerotic plaques. UNC5B clustering correlated positively with inflammatory and MΦ markers. NTN1 protein colocalized with CD68-positive cells of monocytic origin and muscle-actin-specific-antibody (HHF3)-positive cells indicative of SMCs in the plaques and only with SMCs in the control samples. NTN1 protein was highly expressed in the intimal layer of the control vessels.Present findings provide support for the hypothesis that dysregulation of expression of NTN1 in SMCs and its chemorepulsive receptor UNC5B in macrophages are involved in the development of atherosclerosis and unstable plaques. [ABSTRACT FROM AUTHOR]
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- 2013
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12. Myocardial infarction induces early increased remote ADAM8 expression of rat hearts after cardiac arrest.
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Vuohelainen, Vilma, Raitoharju, Emma, Levula, Mari, Lehtimaki, Terho, Pelto-Huikko, Markku, Honkanen, Teemu, Huovila, Ari, Paavonen, Timo, Tarkka, Matti, and Mennander, Ari
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MYOCARDIAL infarction ,GENE expression ,CARDIAC arrest ,LABORATORY rats ,HEART transplantation ,METALLOPROTEINASES ,INFLAMMATION - Abstract
Background. A disintegrin and metalloproteinase-8 (ADAM8) is a potential surrogate of inflammation which has recently been associated with myocardial infarction. We evaluated in a rat cardiac transplantation model whether ischemia-reperfusion injury alone (IRI) or with early regional myocardial infarction (MI) would suffice to induce inflammatory myocardial remodeling and ADAM8 expression. Material and methods. Isogenic heterotopic cardiac transplantation after cardiac arrest was performed to 48 Fischer 344 rats to induce ischemia-reperfusion injury (IRI), of which 27 rats also underwent ligation of the left anterior coronary artery (LAD) of the heart to yield MI. Histology was performed at 0.5, 24 and 48 h after transplantation. ADAM8 was evaluated by qRT-PCR after graft harvesting. Results. After 0.5 and 48 h respectively, edematous intramyocardial artery nuclei and periadventitial inflammation were more prominent in MI after transplantation, as compared with IRI alone and Controls (57.0 vs 40.0 and 5.0; 1.9 vs 1.1 and 0.9, point score units, p < 0.05, respectively). The expression of ADAM-8 was increased in MI as compared with Controls (1.9 vs 1.0, 1.9 fold increase) at 48 h. In grafts with MI, ADAM8 was localized using immunohistochemistry to the vicinity of the area corresponding to the developing infarction as well as in intramyocardial arteries remote to the infarction area. Conclusions. Remote histopathological changes of ischemic cardiac grafts are associated with increased expression of ADAM8 thus emphasizing a global myocardial impact of MI. [ABSTRACT FROM AUTHOR]
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- 2011
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13. A disintegrin and metalloprotease -8 and -15 and susceptibility for ascending aortic dissection.
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Levula, Mari, Paavonen, Timo, Valo, Timo, Pelto-Huikko, Markku, Laaksonen, Reijo, Kahonen, Mika, Huovila, Ari, Lehtimaki, Terho, Tarkka, Matti, and Mennander, Ari A.
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AORTIC dissection , *METALLOPROTEINASES , *AORTA surgery , *EXTRACELLULAR matrix , *AORTITIS , *IMMUNOHISTOCHEMISTRY , *POLYMERASE chain reaction - Abstract
Background. Dilatation of the ascending aorta (AA) is affected by extra-cellular matrix modifications and inflammation. A disintegrin and metalloproteases (ADAMs) may reveal differences between AA and ascending aortic dissection (AD). We characterized the inflammatory histology of AD and AA and examined the role of ADAM8 and -15 in these diseases. Material and methods. Aortic wall histology and immunohistochemistry for leukocytes, T- and B-lymphocytes, plasma cells, macrophages, endothelial cells, smooth muscle cells, cell proliferation, elastase and Van-Gieson-staining were performed to 40 consecutive patients that underwent surgery for AA or AD. The expressions of ADAM8 and -15 mRNA and proteins were evaluated using QRT-PCR and immunohistochemistry. Results. Thirty-four patients were enrolled, of which 29 had AA and five had AD of the ascending aorta. B-cells throughout the aortic wall and intimal plasma cells were more numerous during AD as compared with AA ( p < 0.05). The gene expressions for ADAM8 and -15 were notably lower in AA as compared with AD. The median for down-regulation of ADAM8 and -15 in AA was -2.7 and −1.8, respectively. ADAM8 and -15 were mainly found in the media layer in patients with AD. Two of the patients with AA and increased ADAMs developed AD of the remaining aorta. Conclusions. The involvement of ADAM8 and -15 together with inflammation consisting of B-cells may indicate active remodelling of the aortic wall leading to AD. [ABSTRACT FROM AUTHOR]
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- 2011
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14. Carbonic anhydrases II and XII are up-regulated in osteoclast-like cells in advanced human atherosclerotic plaques—Tampere Vascular Study.
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Oksala, Niku, Levula, Mari, Pelto-Huikko, Markku, Kytömäki, Leena, Soini, Juhani T., Salenius, Juha, Kähönen, Mika, Karhunen, Pekka J., Laaksonen, Reijo, Parkkila, Seppo, and Lehtimäki, Terho
- Abstract
Background and aims. Carbonic anhydrases (CA) play a central role in osteoclast function and bone remodeling by catalyzing the formation of bicarbonate and proton from carbon dioxide. According to previous histochemical studies, advanced atherosclerotic plaques share similarities with bone. However, whether CAs are expressed in plaques is not known. Methods and results. Whole genome expression array of arterial samples ( n = 24) confirmed that several genes indicating osteoblastogenesis and osteoclastogenesis were up-regulated in plaques when compared to control vessel samples from internal thoracic arteries ( n = 6), including CA2 and CA12, expression of which was also verified with quantitative reverse transcription polymerase chain reaction (RT-PCR). In atherosclerotic plaques there was 11.6-fold ( P < 0.0001) and 11.4-fold ( P < 0.0001) up-regulation of CA2 and CA12, compared to controls, respectively. According to quantitative PCR, CA2 expression was elevated in carotid (12.3-fold, P < 0.0001), femoral (13.2-fold, P < 0.01), and aortic plaques (7.5-fold, P < 0.0001). CA12 expression was elevated in carotid (11.6-fold, P < 0.0001), femoral (11.5-fold, P < 0.01), and aortic plaques (9.7-fold, P < 0.0001). CAII, CAXII, and CD68 and tartrate-resistant acid phosphatase (TRAP), a marker of osteoclast-like cells, were found to be co-localized in multinucleated giant cells in the atherosclerotic plaques using immunohistochemistry and double-staining immunofluorescence analysis. Conclusions. The present findings provide evidence for the involvement of CAs in advanced atherosclerosis in osteoclast-like cells of monocyte-macrophage lineage. [ABSTRACT FROM AUTHOR]
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- 2010
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15. Activation of indoleamine 2,3-dioxygenase-induced tryptophan degradation in advanced atherosclerotic plaques: Tampere Vascular Study.
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Niinisalo, Petri, Oksala, Niku, Levula, Mari, Pelto-Huikko, Markku, Järvinen, Otso, Salenius, Juha-Pekka, Kytömäki, Leena, Soini, Juhani T., Kähönen, Mika, Laaksonen, Reijo, Hurme, Mikko, and Lehtimäki, Terho
- Abstract
Objective. We aimed to characterize the expression of indoleamine 2,3-dioxygenase (IDO) or IDO-induced tryptophan degradation-dependent pathways, which may lead to suppression of T cells and possible protection against atherosclerosis. Methods and results. Expression of IDO and IDO-related pathway components was analyzed in advanced human atherosclerotic plaques ( n = 24) and in non-atherosclerotic arteries ( n = 6). Up-regulation of IDO and genes related to the IDO pathway was found to be pronounced in atherosclerotic plaques. Immunohistochemistry demonstrated IDO protein in the atheromatous core and co-distribution with monocyte-macrophages (CD68-positive cells). In gene-set enrichment analysis, the IDO pathway revealed a significant (false discovery rate (FDR) = 0.07) regulatory T cell, fork-head box protein 3 (FoxP3)-initiated CD28-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)-inducible T cell co-stimulator (ICOS)-driven pathway leading to activation of IDO expression in antigen-presenting cells (APCs). Expression of these IDO pathway genes varied between 2.1- and 16.8-fold as compared to control tissues ( P < 0.05 for all). Conclusions. IDO and the IDO-related pathway are important mediators of the immunoinflammatory responses in advanced atherosclerosis offering new viable therapeutic targets for the development of antiatherogenic immunosuppressive therapies. [ABSTRACT FROM AUTHOR]
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- 2010
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16. ADAM8 and its single nucleotide polymorphism 2662 T/G are associated with advanced atherosclerosis and fatal myocardial infarction: Tampere vascular study.
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Levula, Mari, Airla, Niku, Oksala, Niku, Hernesniemi, Jussi A., Pelto-Huikko, Markku, Salenius, Juha-Pekka, Zeitlin, Rainer, Järvinen, Otso, Huovila, Ari-Pekka J., Nikkari, Seppo T., Jaakkola, Olli, Ilveskoski, Erkki, Mikkelsson, Jussi, Perola, Markus, Laaksonen, Reijo, Kytömäki, Leena, Soini, Juhani T., Kähönen, Mika, Parkkinen, Jyrki, and Karhunen, Pekka J.
- Abstract
Objective. Previously, we scanned all 23,000 human genes for differential expression between normal and atherosclerotic tissues and found the involvement of ADAM8. Methods. We investigated the expression of ADAM8 mRNA and protein level in human atherosclerotic tissues and non-atherosclerotic internal thoracic arteries as well as the association of ADAM8 2662 T/G single nucleotide polymorphism (SNP) with the extent of coronary atherosclerosis and with the risk of fatal myocardial infarction. Results. ADAM8 mRNA was up-regulated in carotid, aortic, and femoral atherosclerotic plaques (n=24) when compared with non-atherosclerotic arteries. ADAM8 protein expression was increased in advanced atherosclerotic plaques as compared to control vessels wherein it was localized to macrophages and smooth muscle cells The G allele carriers of the ADAM8 2662 T/G SNP had significantly larger areas of fibrotic, calcified, and complicated plaques in coronary arteries (P=0.027, P=0.011, and P=0.011, respectively) and significantly higher occurrence of myocardial infarction (MI) (P=0.004) and fatal pre-hospital MI (P=0.003) than did the TT homozygotes. Conclusion. ADAM8 is a promising candidate to be involved in atherosclerosis, and its 2662 T/G allelic variant significantly associates with advanced atherosclerotic lesion areas and MI. [ABSTRACT FROM AUTHOR]
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- 2009
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17. ADAM-9, ADAM-15, and ADAM-17 are upregulated in macrophages in advanced human atherosclerotic plaques in aorta and carotid and femoral arteries—Tampere vascular study.
- Author
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Oksala, Niku, Levula, Mari, Airla, Nina, Pelto-Huikko, Markku, Ortiz, Rebekka M., Järvinen, Otso, Salenius, Juha-Pekka, Ozsait, Bilge, Komurcu-Bayrak, Evrim, Erginel-Unaltuna, Nihan, Huovila, Ari-Pekka J., Kytömäki, Leena, Soini, Juhani T., Kähönen, Mika, Karhunen, Pekka J., Laaksonen, Reijo, and Lehtimäki, Terho
- Abstract
Background and aims. The expression of disintegrin and metalloprotease ADAM-9, ADAM-15, and ADAM-17 has been associated with cell-cell, cell-platelet, and cell-matrix interactions and inflammation. They are possibly implicated in the pathophysiology of atherosclerosis. Methods and results. Whole-genome expression array and quantitative real-time polymerase chain reaction (PCR) analysis confirmed that ADAM-9, ADAM-15, and ADAM-17 are upregulated in advanced human atherosclerotic lesions in samples from carotid, aortic, and femoral territories compared to samples from internal thoracic artery (ITA) free of atherosclerotic plaques. Western analysis indicated that the majority of these ADAMs were in the catalytically active form. ADAM-9, ADAM-15, and ADAM-17-expressing cells were shown to co-localize with CD68-positive cells of monocytic origin in the atherosclerotic plaques using immunohistochemistry and double-staining immunofluorescence analysis. Co-localization was demonstrated in all vascular territories. In the carotid territory, cells expressing the ADAMs co-distributed also with smooth muscle cells and, in femoral territory, with CD31-positive endothelial cells, indicating that the ADAM expression pattern depends on vascular bed territory. Conclusions. Present findings provide strong evidence for the involvement of catalytically active ADAM-9, ADAM-15, and ADAM-17 in advanced atherosclerosis, most notably associated with cells of monocytic origin. [ABSTRACT FROM AUTHOR]
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- 2009
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18. Differentially expressed genes and canonical pathway expression in human atherosclerotic plaques - Tampere Vascular Study.
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Sulkava, Miska, Raitoharju, Emma, Levula, Mari, Seppälä, Ilkka, Lyytikäinen, Leo-Pekka, Mennander, Ari, Järvinen, Otso, Zeitlin, Rainer, Salenius, Juha-Pekka, Illig, Thomas, Klopp, Norman, Mononen, Nina, Laaksonen, Reijo, Kähönen, Mika, Oksala, Niku, and Lehtimäki, Terho
- Abstract
Cardiovascular diseases due to atherosclerosis are the leading cause of death globally. We aimed to investigate the potentially altered gene and pathway expression in advanced peripheral atherosclerotic plaques in comparison to healthy control arteries. Gene expression analysis was performed (Illumina HumanHT-12 version 3 Expression BeadChip) for 68 advanced atherosclerotic plaques (15 aortic, 29 carotid and 24 femoral plaques) and 28 controls (left internal thoracic artery (LITA)) from Tampere Vascular Study. Dysregulation of individual genes was compared to healthy controls and between plaques from different arterial beds and Ingenuity pathway analysis was conducted on genes with a fold change (FC) > ±1.5 and false discovery rate (FDR) < 0.05. 787 genes were significantly differentially expressed in atherosclerotic plaques. The most up-regulated genes were osteopontin and multiple MMPs, and the most down-regulated were cell death-inducing DFFA-like effector C and A (CIDEC, CIDEA) and apolipoprotein D (FC > 20). 156 pathways were differentially expressed in atherosclerotic plaques, mostly inflammation-related, especially related with leukocyte trafficking and signaling. In artery specific plaque analysis 50.4% of canonical pathways and 41.2% GO terms differentially expressed were in common for all three arterial beds. Our results confirm the inflammatory nature of advanced atherosclerosis and show novel pathway differences between different arterial beds. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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19. miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study
- Author
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Raitoharju, Emma, Lyytikäinen, Leo-Pekka, Levula, Mari, Oksala, Niku, Mennander, Ari, Tarkka, Matti, Klopp, Norman, Illig, Thomas, Kähönen, Mika, Karhunen, Pekka J., Laaksonen, Reijo, and Lehtimäki, Terho
- Subjects
- *
ATHEROSCLEROTIC plaque , *GENETIC regulation , *NON-coding RNA , *GENE expression , *GENE targeting , *MESSENGER RNA - Abstract
Abstract: Objective: MicroRNAs are small non-coding RNAs that inversely regulate their target gene expression. The whole miRNA profile of human atherosclerotic plaques has not been studied previously. The aim of this study was to investigate the miRNA expression profile in human atherosclerotic plaques as compared to non-atherosclerotic left internal thoracic arteries (LITA), and to connect this expression to the processes in atherosclerosis. Methods: The miRNA expression profiles of six LITAs and 12 atherosclerotic plaques obtained from aortic, carotid, and femoral atherosclerotic arteries from Tampere Vascular Study were analyzed. The analyses were performed with Agilent''s miRNA Microarray. The expression levels of over 4-fold up-regulated miRNAs were verified with qRT-PCR from a larger population (n =50). Messenger RNA levels were analyzed with Illumina''s Expression BeadChip to study miRNA target expression. Results: Ten miRNAs were found to be differently expressed in atherosclerotic plaques when compared to controls (p <0.05). The expression of miR-21, -34a, -146a, -146b-5p, and -210 was verified and found to be significantly up-regulated in atherosclerotic arteries versus LITAs (p <0.001, fold changes 4.61, 2.55, 2.87, 2.82, and 3.92, respectively). Several predicted targets of these miRNAs were down-regulated, and gene set enrichment analysis showed several pathways which could be differently expressed due to this miRNA profile. Conclusions: The microRNA expression profile differs significantly between atherosclerotic plaques and control arteries. The most up-regulated miRNAs are involved in processes known to be connected to atherosclerosis. Interfering with the miRNA expression in the artery wall is a potential way to affect atherosclerotic plaque and cardiovascular disease development. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
20. Common variation in the ADAM8 gene affects serum sADAM8 concentrations and the risk of myocardial infarction in two independent cohorts
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Raitoharju, Emma, Seppälä, Ilkka, Levula, Mari, Kuukasjärvi, Pekka, Laurikka, Jari, Nikus, Kjell, Huovila, Ari-Pekka J., Oksala, Niku, Klopp, Norman, Illig, Thomas, Laaksonen, Reijo, Karhunen, Pekka J., Viik, Jari, Lehtinen, Rami, Pelto-Huikko, Markku, Tarkka, Matti, Kähönen, Mika, and Lehtimäki, Terho
- Subjects
- *
MYOCARDIAL infarction risk factors , *GENETIC polymorphisms , *METALLOPROTEINASES , *ANGIOGRAPHY , *ATHEROSCLEROTIC plaque , *COHORT analysis , *ENZYME-linked immunosorbent assay - Abstract
Abstract: Objective: The single nucleotide polymorphism (SNP) rs2995300 in the metalloproteinase-disintegrin gene ADAM8 has been shown to affect the areas of complicated coronary plaques and the risk of fatal myocardial infarction (MI) in men. This study was set up to further investigate the role of ADAM8 in MI. Aim: To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk. Methods: Samples from the Finnish cardiovascular study (FINCAVAS, N =2156) and the angiography and genes study (ANGES, N =1000) were genotyped. Serum sADAM8 concentrations were determined with ELISA (N =443). ADAM8 mRNA levels in atherosclerotic plaques were analysed from the tampere vascular study (TVS, N =53) samples. Results: A significantly increased MI risk for carriers of the rs2995300C allele and the rs2275725 A allele was revealed in the meta-analysis of the ANGES and FINCAVAS patient data (OR=1.42, P <0.001 and OR=1.43, P <0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations. Conclusions: The risk alleles of the investigated ADAM8 SNPs were associated with elevated sADAM8 serum levels and MI risk. The present results implicate ADAM8 in the development of CVDs and suggest its prognostic and therapeutic potential. [Copyright &y& Elsevier]
- Published
- 2011
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21. Niemann–Pick type C fibroblasts have a distinct microRNA profile related to lipid metabolism and certain cellular components
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Ozsait, Bilge, Komurcu-Bayrak, Evrim, Levula, Mari, Erginel-Unaltuna, Nihan, Kähönen, Mika, Rai, Myriam, Lehtimäki, Terho, and Laaksonen, Reijo
- Subjects
- *
FIBROBLASTS , *NIEMANN-Pick diseases , *NON-coding RNA , *GENE targeting , *LIPID metabolism , *ENDOPLASMIC reticulum , *GENETIC regulation , *PATHOLOGICAL physiology - Abstract
Abstract: MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at post-transcriptional level. Dysregulation of miRNA expression may lead to severe pathophysiologies in human cells. Niemann–Pick type C (NPC) disease is a complex lipid storage disease characterized by late endosomal–lysosomal accumulation of multiple lipid molecules. Our aim was to characterize the miRNA profile in NPC fibroblasts as they may play an active role in the NPC disease associated changes in the cellular physiology. To investigate the miRNA expression, total RNAs were isolated from cultured human NPC fibroblasts and healthy fibroblasts and then, TaqMan Low-Density Array system containing 365 mature human miRNAs was used. Expression differences between the healthy and NPC cells were detected according to the relative quantification values. Target genes were predicted by using three different algorithms and classified regarding NPC related biological processes and cellular components. We found that three miRNAs, miR-196a, miR-196b and miR-296 were up-regulated (>3.5-fold increase, p <0.05) whereas 38 miRNAs were significantly down-regulated in NPC cells (>3.5-fold decrease, p <0.05). Among these non-coding RNAs, miR-98 was the most down-regulated (−33.3-fold) miRNA and miR-143, the lipid biosynthesis associated miRNA, had a 20-fold decreased expression in the NPC cells. Additionally, gene ontology analyses of the target genes suggested a distinct role for each miRNA. Our results show that NPC fibroblasts have an altered miRNA expression profile and certain miRNAs have importance in disease pathogenesis as well as the therapeutic capacity to correct lipid related pathophysiologies in the NPC cells. [Copyright &y& Elsevier]
- Published
- 2010
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22. A comparison of the accuracy of Illumina HumanHT-12 v3 Expression BeadChip and TaqMan qRT-PCR gene expression results in patient samples from the Tampere Vascular Study
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Raitoharju, Emma, Seppälä, Ilkka, Lyytikäinen, Leo-Pekka, Levula, Mari, Oksala, Niku, Klopp, Norman, Illig, Thomas, Laaksonen, Reijo, Kähönen, Mika, and Lehtimäki, Terho
- Subjects
- *
ATHEROSCLEROTIC plaque , *GENE expression , *REVERSE transcriptase polymerase chain reaction , *COMPARATIVE studies , *STATISTICAL correlation , *MEDICAL statistics - Abstract
Abstract: Aims: This study was set up to compare the accuracy, sensitivity and specificity of gene expression results between the Illumina HumanHT-12 v3 Expression BeadChip (GWE) and the TaqMan qRT-PCR low-density array (LDA) in atherosclerotic plaques. Methods: Gene expression levels of 196 genes were determined from 22 atherosclerotic samples and 6 controls with both the GWE and the LDA. Results: The accuracies of GWE in comparison to that of qRT-PCR for absolute fold changes (FC) 1.2, 1.6, 2.0 and 3.0 between cases and controls were 73.5%, 79.1%, 72.4% and 60.7%, respectively. The correlation of expression measurements between these methods was good (r = 0.87, y = 0.151 + 0.586x), and the Bland–Altman plot showed that for highly up- or down-regulated transcripts, GWE yields lower absolute FC values than LDA. Conclusion: Gene expression results obtained with the GWE are replicated with high accuracy in LDA, even for technically demanding atherosclerotic samples. [Copyright &y& Elsevier]
- Published
- 2013
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23. Proprotein convertases in human atherosclerotic plaques: The overexpression of FURIN and its substrate cytokines BAFF and APRIL
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Turpeinen, Hannu, Raitoharju, Emma, Oksanen, Anna, Oksala, Niku, Levula, Mari, Lyytikäinen, Leo-Pekka, Järvinen, Otso, Creemers, John W.M., Kähönen, Mika, Laaksonen, Reijo, Pelto-Huikko, Markku, Lehtimäki, Terho, and Pesu, Marko
- Subjects
- *
ATHEROSCLEROTIC plaque , *ENZYMES , *GENE expression , *CYTOKINES , *CHOLESTEROL metabolism , *ATHEROSCLEROSIS , *IMMUNOHISTOCHEMISTRY - Abstract
Abstract: Background: Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave proproteins into mature end products. Previously, MBTPS1 and PCSK9 have been shown to regulate cholesterol metabolism and LDL receptor recycling, whereas FURIN and PCSK5 have been suggested to inactivate lipases and regulate inflammation in atherosclerosis. Here, we systematically analyzed the expression of PCSKs and their targets in advanced atherosclerotic plaques. Methods and results: Microarray and quantitative real-time PCR experiments showed that FURIN (42.86 median fold, p =2.1e−8), but no other PCSK, is universally overexpressed in the plaques of different vascular regions. The mRNA expression screen of PCSK target proteins in plaques identified many known factors, but it also identified the significant upregulation of the previously overlooked furin-processed B cell activating cytokines APRIL (TNFSF13, 2.52 median fold, p =3.0e−5) and BAFF (TNFSF13B, 2.97 median fold, p =7.6e−6). The dysregulation of FURIN did not associate with its htSNPs or the previously reported regulatory SNP (−229, rs4932178) in the promoter. Immunohistochemistry experiments showed the upregulation of FURIN in the plaque lymphocytes and macrophages where it was co-expressed with BAFF/TNFSF13B and APRIL/TNFSF13. Conclusions: Our data unequivocally show that FURIN is the primary PCSK that is dysregulated in the immune cells of advanced human atherosclerotic plaques, which implies a role for this enzyme in plaque pathology. Therefore, drugs that inhibit FURIN in arteries may modulate the course of this disease. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
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24. Differentially expressed genes and canonical pathways in the ascending thoracic aortic aneurysm - The Tampere Vascular Study.
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Sulkava M, Raitoharju E, Mennander A, Levula M, Seppälä I, Lyytikäinen LP, Järvinen O, Illig T, Klopp N, Mononen N, Laaksonen R, Kähönen M, Oksala N, and Lehtimäki T
- Subjects
- Aged, Aorta, Thoracic metabolism, Aorta, Thoracic pathology, Aortic Aneurysm, Thoracic metabolism, Aortic Aneurysm, Thoracic pathology, Female, Gene Ontology, Humans, Male, Middle Aged, Aortic Aneurysm, Thoracic genetics, Signal Transduction, Transcriptome
- Abstract
Ascending thoracic aortic aneurysm (ATAA) is a multifactorial disease with a strong inflammatory component. Surgery is often required to prevent aortic rupture and dissection. We performed gene expression analysis (Illumina HumanHT-12 version 3 Expression BeadChip) for 32 samples from ATAA (26 without/6 with dissection), and 28 left internal thoracic arteries (controls) collected in Tampere Vascular study. We compared expression profiles and conducted pathway analysis using Ingenuity Pathway Analysis (IPA) to reveal differences between ATAA and a healthy artery wall. Almost 5000 genes were differentially expressed in ATAA samples compared to controls. The most downregulated gene was homeobox (HOX) A5 (fold change, FC = -25.3) and upregulated cadherin-2 (FC = 12.6). Several other HOX genes were also found downregulated (FCs between -25.3 and -1.5, FDR < 0.05). 43, mostly inflammatory, canonical pathways in ATAA were found to be significantly (p < 0.05, FDR < 0.05) differentially expressed. The results remained essentially the same when the 6 dissected ATAA samples were excluded from the analysis. We show for the first time on genome level that ATAA is an inflammatory process, revealing a more detailed molecular pathway level pathogenesis. We propose HOX genes as potentially important players in maintaining aortic integrity, altered expression of which might be important in the pathobiology of ATAA.
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- 2017
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25. Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque.
- Author
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Fan YM, Hernesniemi J, Oksala N, Levula M, Raitoharju E, Collings A, Hutri-Kähönen N, Juonala M, Marniemi J, Lyytikäinen LP, Seppälä I, Mennander A, Tarkka M, Kangas AJ, Soininen P, Salenius JP, Klopp N, Illig T, Laitinen T, Ala-Korpela M, Laaksonen R, Viikari J, Kähönen M, Raitakari OT, and Lehtimäki T
- Subjects
- Adult, Alleles, Apolipoproteins B blood, Atherosclerosis pathology, Cholesterol, LDL blood, Female, Genotype, Haplotypes, Humans, Male, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Sex Factors, Atherosclerosis genetics, Lipid Metabolism physiology, Upstream Stimulatory Factors genetics
- Abstract
Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.
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- 2014
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26. Bacterial DNA signatures in carotid atherosclerosis represent both commensals and pathogens of skin origin.
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Renko J, Koskela KA, Lepp PW, Oksala N, Levula M, Lehtimäki T, Solakivi T, Kunnas T, Nikkari S, and Nikkari ST
- Subjects
- Aged, Aged, 80 and over, DNA, Ribosomal, Female, Humans, Male, Middle Aged, Polymerase Chain Reaction, Sequence Analysis, DNA, Actinobacteria isolation & purification, Carotid Artery Diseases microbiology, DNA, Bacterial isolation & purification, Metagenome, Skin microbiology
- Abstract
Infectious agents have been suggested to be involved in atherosclerosis. By using a novel subtraction broad-range PCR approach, we defined bacterial DNA signatures in surgically removed sterile carotid artery endarterectomy plaques of patients with carotid atherosclerosis. Eighty partial bacterial 16S rDNA nucleotide sequences from eight patients were studied. Furthermore, 34 clones representing 21 bacterial sequence-types from the reagents used for DNA extraction and PCR amplification were determined. After subtraction of these potential methodological contaminants, 23 bacterial sequence-types were considered as clinically relevant findings. The most prominent phylum, Actinobacteria, accounted for 74% of these relevant sequences. Furthermore, according to the Human Microbiome project database, interestingly, nearly all (94%) of the sequences were associated with the human skin microbiome.
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- 2013
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27. Genes involved in systemic and arterial bed dependent atherosclerosis--Tampere Vascular study.
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Levula M, Oksala N, Airla N, Zeitlin R, Salenius JP, Järvinen O, Venermo M, Partio T, Saarinen J, Somppi T, Suominen V, Virkkunen J, Hautalahti J, Laaksonen R, Kähönen M, Mennander A, Kytömäki L, Soini JT, Parkkinen J, Pelto-Huikko M, and Lehtimäki T
- Subjects
- Aged, Arteries metabolism, Arteries physiopathology, Case-Control Studies, Female, Finland, Genomics, Humans, Male, Organ Specificity, Plaque, Atherosclerotic pathology, Plaque, Atherosclerotic physiopathology, Arteries pathology, Gene Expression Profiling, Plaque, Atherosclerotic genetics
- Abstract
Background: Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed., Methodology/principal Findings: We characterized the genes generally involved in human advanced atherosclerotic (AHA type V-VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25)., Conclusions: This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds.
- Published
- 2012
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28. Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death.
- Author
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Fan YM, Karhunen PJ, Levula M, Ilveskoski E, Mikkelsson J, Kajander OA, Järvinen O, Oksala N, Thusberg J, Vihinen M, Salenius JP, Kytömäki L, Soini JT, Laaksonen R, and Lehtimäki T
- Abstract
Background: Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, SREBF-2 1784G>C (rs2228314) and SCAP 2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD)., Methods: Whole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33-69 years) Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the SREBF-2 and SCAP genotypes., Results: Whole genome expression profiling showed a significant (p = 0.02) down-regulation of SREBF-2 in atherosclerotic carotid plaques (types IV-V), but not in the aorta or femoral arteries (p = NS for both), as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the SREBF-2 1784G>C and the SCAP 2386A>G genotype was observed on the risk of SCD (p = 0.046). Men with the SREBF-2 C allele and the SCAP G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07-6.71), compared to SCAP AA homologous subjects carrying the SREBF-2 C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the results were not statistically significant., Conclusion: The results suggest that the allelic variants (SREBF-2 1784G>C and SCAP 2386A>G) in the cholesterol homeostasis regulating SREBF-SCAP pathway may contribute to SCD in early middle-aged men.
- Published
- 2008
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29. Gene expression profiles in Finnish twins with multiple sclerosis.
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Särkijärvi S, Kuusisto H, Paalavuo R, Levula M, Airla N, Lehtimäki T, Kaprio J, Koskenvuo M, and Elovaara I
- Subjects
- Diseases in Twins metabolism, Finland, Gene Expression Profiling, Humans, Multiple Sclerosis metabolism, Twins, Monozygotic, Up-Regulation, Diseases in Twins genetics, Multiple Sclerosis genetics
- Abstract
Background: Since genetic alterations influencing susceptibility to multiple sclerosis (MS), the most common autoimmune demyelinating disease of the central nervous system (CNS), are as yet poorly understood, the purpose of this study was to identify genes responsible for MS by studying monozygotic (MZ) twin pairs discordant for MS., Methods: In order to identify genes involved in MS development, the gene expression profiles in blood mononuclear cells obtained from eight MZ twin pairs discordant for MS were analyzed by cDNA microarray technology detecting the expression of 8 300 genes. The twins were collected from the Finnish Twin Cohort Study and both affected subjects and their healthy siblings underwent neurological evaluation and cerebral and spinal magnetic resonance imaging. Gene expressions were confirmed by relative quantitative reverse transcription PCR., Results: It appeared that 25 genes were at least two-fold up-regulated and 15 genes down-regulated in 25% (2/8) of twins with MS when compared to their healthy siblings. Moreover, 6/25 genes were up-regulated in 40% of MS twins and one gene, interferon alpha-inducible protein (clone IFI-6-16) (G1P3), in 50% of them. The six most constantly expressed genes are (1) G1P3, (2) POU domain, class 3, transcription factor 1, (3) myxovirus resistance 2, (4) lysosomal-associated multispanning membrane protein-5, (5) hemoglobin alpha 2 and (6) hemoglobin beta., Conclusion: Over two-fold up-regulation of these six genes in almost half of MZ twins with MS suggests their role in MS pathogenesis. Studies using MZ MS twins obtained from genetically homogeneous population offer a unique opportunity to explore the genetic nature of MS.
- Published
- 2006
- Full Text
- View/download PDF
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