Browsing by Subject "atherosclerosis"

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  • Nguyen, Su Duy; Javanainen, Matti; Rissanen, Sami; Zhao, Hongxia; Huusko, Jenni; Kivelä, Annukka M.; Ylä-Herttuala, Seppo; Navab, Mohamad; Fogelman, Alan M.; Vattulainen, Ilpo; Kovanen, Petri T.; Öörni, Katariina (2015)
    Lipolytic modification of LDL particles by SMase generates LDL aggregates with a strong affinity for human arterial proteoglycans and may so enhance LDL retention in the arterial wall. Here, we evaluated the effects of apoA-I mimetic peptide 4F on structural and functional properties of the SMase-modified LDL particles. LDL particles with and without 4F were incubated with SMase, after which their aggregation, structure, and proteoglycan binding were analyzed. At a molar ratio of L-4F to apoB-100 of 2.5 to 20: 1, 4F dose-dependently inhibited SMase-induced LDL aggregation. At a molar ratio of 20: 1, SMase-induced aggregation was fully blocked. Binding of 4F to LDL particles inhibited SMase-induced hydrolysis of LDL by 10% and prevented SMase-induced LDL aggregation. In addition, the binding of the SMase-modifi ed LDL particles to human aortic proteoglycans was dose-dependently inhibited by pretreating LDL with 4F. The 4F stabilized apoB-100 conformation and inhibited SMase-induced conformational changes of apoB-100. Molecular dynamic simulations showed that upon binding to protein-free LDL surface, 4F locally alters membrane order and fluidity and induces structural changes to the lipid layer. Collectively, 4F stabilizes LDL particles by preventing the SMase-induced conformational changes in apoB-100 and so blocks SMase-induced LDL aggregation and the resulting increase in LDL retention.
  • Nissilä, Eija; Hakala, Pipsa; Leskinen, Katarzyna; Roig, Angela; Syed, Shahan; Van Kessel, Kok P. M.; Metso, Jari; De Haas, Carla J. C.; Saavalainen, Päivi; Meri, Seppo; Chroni, Angeliki; Van Strijp, Jos A. G.; Öörni, Katariina; Jauhiainen, Matti; Jokiranta, T. Sakari; Haapasalo, Karita (2018)
    The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Factor H (FH), the main AP regulator in plasma. Although complement is known to play a role in atherosclerosis, the mechanisms of its contribution are not fully understood. Since FH via its domains 5-7 binds apoliporotein E (apoE) and macrophages produce apoE we examined how FH could be involved in the antiatherogenic effects of apoE. We used blood peripheral monocytes and THP-1 monocyte/macrophage cells which were also loaded with acetylated low-density lipoprotein (LDL) to form foam cells. Binding of FH and apoE on these cells was analyzed by flow cytometry. High-density lipoprotein (HDL)-mediated cholesterol efflux of activated THP-1 cells was measured and transcriptomes of THP-1 cells using mRNA sequencing were determined. We found that binding of FH to human blood monocytes and cholesterol-loaded THP-1 macrophages increased apoE binding to these cells. Preincubation of fluorescent cholesterol labeled THP-1 macrophages in the presence of FH increased cholesterol efflux and cholesterol-loaded macrophages displayed reduced transcription of proinflammatory/proatherogenic factors and increased transcription of anti-inflammatory/anti-atherogenic factors. Further incubation of THP-1 cells with serum reduced C3b/iC3b deposition. Overall, our data indicate that apoE and FH interact with monocytic cells in a concerted action and this interaction reduces complement activation and inflammation in the atherosclerotic lesions. By this way FH may participate in mediating the beneficial effects of apoE in suppressing atherosclerotic lesion progression.
  • Gruzdaitis, Päivi (Helsingfors universitet, 2011)
    Complications of atherosclerosis such as myocardial infarction and stroke are the primary cause of death in Western societies. The development of atherosclerotic lesions is a complex process, including endothelial cell dysfunction, inflammation, extracellular matrix alteration and vascular smooth muscle cell (VSMC) proliferation and migration. Various cell cycle regulatory proteins control VSMC proliferation. Protein kinases called cyclin dependent kinases (CDKs) play a major role in regulation of cell cycle progression. At specific phases of the cell cycle, CDKs pair with cyclins to become catalytically active and phosphorylate numerous substrates contributing to cell cycle progression. CDKs are also regulated by cyclin dependent kinase inhibitors, activating and inhibitory phosphorylation, proteolysis and transcription factors. This tight regulation of cell cycle is essential; thus its deregulation is connected to the development of cancer and other proliferative disorders such as atherosclerosis and restenosis as well as neurodegenerative diseases. Proteins of the cell cycle provide potential and attractive targets for drug development. Consequently, various low molecular weight CDK inhibitors have been identified and are in clinical development. Tylophorine is a phenanthroindolizidine alkaloid, which has been shown to inhibit the growth of several human cancer cell lines. It was used in Ayurvedic medicine to treat inflammatory disorders. The aim of this study was to investigate the effect of tylophorine on human umbilical vein smooth muscle cell (HUVSMC) proliferation, cell cycle progression and the expression of various cell cycle regulatory proteins in order to confirm the findings made with tylophorine in rat cells. We used several methods to determine our hypothesis, including cell proliferation assay, western blot and flow cytometric cell cycle distribution analysis. We demonstrated by cell proliferation assay that tylophorine inhibits HUVSMC proliferation dose-dependently with an IC50 value of 164 nM ± 50. Western blot analysis was used to determine the effect of tylophorine on expression of cell cycle regulatory proteins. Tylophorine downregulates cyclin D1 and p21 expression levels. The results of tylophorine's effect on phosphorylation sites of p53 were not consistent. More sensitive methods are required in order to completely determine this effect. We used flow cytometric cell cycle analysis to investigate whether tylophorine interferes with cell cycle progression and arrests cells in a specific cell cycle phase. Tylophorine was shown to induce the accumulation of asynchronized HUVSMCs in S phase. Tylophorine has a significant effect on cell cycle, but its role as cell cycle regulator in treatment of vascular proliferative diseases and cancer requires more experiments in vitro and in vivo.
  • Vuorio, Alpo; Kovanen, Petri T. (2018)
    This review covers the current knowledge about plant stanol esters as a dietary treatment option for heterozygous familial hypercholesterolemia (he-FH) children. The current estimation of the prevalence of he-FH is about one out of 200-250 persons. In this autosomal dominant disease, the concentration of plasma low-density lipoprotein cholesterol (LDL-C) is strongly elevated since birth. Quantitative coronary angiography among he-FH patients has revealed that stenosing atherosclerotic plaques start to develop in he-FH males in their twenties and in he-FH females in their thirties, and that the magnitude of the plaque burden predicts future coronary events. The cumulative exposure of coronary arteries to the lifelong LDL-C elevation can be estimated by calculating the LDL-C burden (LDL-C level x years), and it can also be used to demonstrate the usefulness of dietary stanol ester treatment. Thus, when compared with untreated he-FH patients, the LDL-C burden of using statin from the age of 10 is 15% less, and if he-FH patients starts to use dietary stanol from six years onwards and a combination of statin and dietary stanol from 10 years onwards, the LDL-C burden is 21% less compared to non-treated he-FH patients. We consider dietary stanol treatment of he-FH children as a part of the LDL-C-lowering treatment package as safe and cost-effective, and particularly applicable for the family-centered care of the entire he-FH families.
  • Sundholm, Johnny K. M.; Suominen, Anu; Sarkola, Taisto; Jahnukainen, Kirsi (2020)
    The long-term vascular effects following childhood hematopoietic stem cell transplantation (HSCT) are not well characterized. We compared arterial wall morphology and function using very-high resolution ultrasound (25-55 MHz) in 62 patients following autologous (n= 19) or allogenic (n= 43) HSCT for childhood malignancies and hematological disease (median age 25.9 years, IQR 21.1-30.1; median follow-up time 17.5 years IQR 14.1-23.0) with an age matched healthy control group (n= 44). Intima-media thickness of carotid (CIMT 0.49 +/- 0.11 vs. 0.42 +/- 0.06 mm,p<0.001), brachial, femoral, radial arteries, and local carotid stiffness, but not adventitial thickness, were increased (p<0.001). Diffuse intimal thickening (>0.06 mm) of femoral or radial arteries (n= 17) and subclinical carotid or femoral plaques (n= 18) were more common (p<0.001). Radiation predicted plaques (p<0.001) and local carotid stiffness (p<0.001), but not intimal thickening. CIMT was predicted by age, BMI >30 kg/m(2), hsCRP >2.5 mg/L, hypertension, HbA1c > 42 mmol/L, and cumulative anthracycline >150 mg/m(2). Cumulative metabolic syndrome criteria and cardiovascular disease (CVD) risk factors were more common among HSCT and related with CIMT (p<0.001), but CIMT was similar among controls and HSCT without CVD risk factors. Long-term childhood HSCT survivors show early arterial aging related with radiation, metabolic, and CVD risk factors. Prevention of risk factors could potentially decelerate early arterial wall thickening.
  • Vuorio, A; Ramaswami, U; Holven, KB (2021)
  • Bertone-Johnson, Elizabeth R.; Virtanen, Jyrki K.; Nurmi, Tarja; Niskanen, Leo; Mursu, Jaakko; Voutilainen, Sari; Ronkainen, Kimmo; Kauhanen, Jussi; Tuomainen, Tomi-Pekka (2018)
    Recent studies of perimenopausal women suggest that follicle-stimulating hormone (FSH) levels may be associated with atherosclerosis, independent of estradiol. Whether FSH is related to atherosclerosis in older postmenopausal women, who have completed the menopausal transition, remains unknown. We assessed the relationship of serum FSH and estradiol levels with carotid artery intima-media thickness (IMT) among 587 postmenopausal participants in the Kuopio Ischemic Heart Disease Risk Factor Study (Kuopio, Finland). Participants were aged 53-73 years and not using hormone therapy at baseline (1998-2001). Mean IMT was measured via high-resolution ultrasonography. We observed a significant inverse association between FSH levels and IMT. Mean IMTs among women in quartiles 1-4 of FSH were 0.94 mm, 0.91 mm, 0.87 mm, and 0.85 mm, respectively (P-trend <0.001). After adjustment for age, estradiol, testosterone, body mass index (weight (kg)/height (m)(2)), lipids, and other factors, FSH levels remained significantly associated with IMT (regression coefficients for quartiles 2-4 vs. quartile 1 were -0.038, -0.045, and -0.062, respectively; P-trend = 0.01). Findings were strongest in women aged 64-73 years (P-trend = 0.006) and did not vary by body mass index. In contrast, estradiol levels were not related to IMT. In summary, high postmenopausal FSH levels were associated with a lower atherosclerotic burden, independent of estradiol, adiposity, and other factors. Our findings warrant replication and the further exploration of potential underlying mechanisms.
  • Litwin, Linda; Sundholm, Johnny K. M.; Meinilä, Jelena; Kulmala, Janne; Tammelin, Tuija H.; Rönö, Kristiina; Koivusalo, Saila B.; Eriksson, Johan G.; Sarkola, Taisto (2021)
    Background: Heredity and family-shared lifestyle contribute to cardiovascular risk, but the magnitude of their influence on arterial structure and function in early childhood is unknown. We aimed to assess associations between child and maternal ideal cardiovascular health, maternal subclinical atherosclerosis, and child arterial phenotype. Methods: Cross-sectional analysis of 201 mother-child pairs originating from the Finnish Gestational Diabetes Prevention Study (RADIEL) longitudinal cohort was done at child age 6.1 +/- 0.5 years with assessments of ideal cardiovascular health (BMI, blood pressure, fasting glucose, total cholesterol, diet quality, physical activity, smoking), body composition, very-high frequency ultrasound of carotid arteries (25 and 35 MHz), and pulse wave velocity. Results: We found no association between child and maternal ideal cardiovascular health but report evidence of particular metrics correlations: total cholesterol (r=0.24, P=0.003), BMI (r=0.17, P=0.02), diastolic blood pressure (r=0.15, P=0.03), and diet quality (r=0.22, P=0.002). Child arterial phenotype was not associated with child or maternal ideal cardiovascular health. In the multivariable regression explanatory model adjusted for child sex, age, systolic blood pressure, lean body mass, and body fat percentage, child carotid intima-media thickness was independently associated only with maternal carotid intima-media thickness (0.1 mm increase [95% CI 0.05, 0.21, P=0.001] for each 1 mm increase in maternal carotid intima-media thickness). Children of mothers with subclinical atherosclerosis had decreased carotid artery distensibility (1.1 +/- 0.2 vs 1.2 +/- 0.2%/10 mmHg, P=0.01) and trend toward increased carotid intima-media thickness (0.37 +/- 0.04 vs 0.35 +/- 0.04 mm, P=0.06). Conclusion: Ideal Cardiovascular Health metrics are heterogeneously associated in mother-child pairs in early childhood. We found no evidence of child or maternal Ideal Cardiovascular Health effect on child arterial phenotype. Maternal carotid intima-media thickness predicts child carotid intima-media thickness, but the underlying mechanisms remain unclear. Maternal subclinical atherosclerosis is associated with local carotid arterial stiffness in early childhood.
  • Gylling, Helena; Strandberg, Timo E.; Kovanen, Petri T.; Simonen, Piia (2020)
    Atherosclerotic cardiovascular diseases (ASCVDs) cause every fifth death worldwide. However, it is possible to prevent the progression of ASCVDs by reducing circulating concentrations of low-density lipoprotein cholesterol (LDL-C). Recent large meta-analyses demonstrated that by reducing the dietary intake of saturated fat and cholesterol, it is possible to reduce the risk of ASCVD events. Plant stanols, as fatty-acid esters, were developed as a dietary adjunct to reduce LDL-C levels as part of a heart-healthy diet. They reduce cholesterol absorption so that less cholesterol is transported to the liver, and the expression of LDL receptors is upregulated. Ultimately, LDL-C concentrations are reduced on average by 9-12% by consuming 2-3 g of plant stanol esters per day. In this review, we discuss recent information regarding the prevention of ASCVDs with a focus on dietary means. We also present new estimates on the effect of plant stanol ester consumption on LDL-C levels and the risk of ASCVD events. Plant stanol esters as part of a heart-healthy diet plausibly offer a means to reduce the risk of ASCVD events at a population level. This approach is not only appropriate for subjects with a high risk of ASCVD, but also for subjects at an apparently lower risk to prevent subclinical atherosclerosis.
  • Simonen, Piia; Arte, Elisa; Gylling, Helena (2021)
    Dietary modifications including plant stanol ester consumption are recommended measures to control serum and low-density lipoprotein (LDL)-cholesterol concentrations, but obesity can affect their responses. We investigated whether body mass index (BMI) affects serum cholesterol levels during plant stanol (mainly sitostanol) ester consumption. This ad hoc analysis was based on earlier results of a cross-over, randomized controlled trial of postmenopausal women consuming rapeseed oil-based margarine without or with plant stanol ester (3 g plant stanols/day) for seven weeks. We classified the subjects as normal-weight (BMI 25 kg/m(2), n = 11, mean 28.4 kg/m(2)), and recalculated the results, focusing on cholesterol absorption, cholesterol synthesis, and fecal steroid outputs. Serum cholesterol levels were similar in the groups during the control diet. Plant stanol ester reduced serum cholesterol by 0.63 +/- 0.19 mmol/L (11%) in normal-weight and by 0.75 +/- 0.13 mmol/L (12%) in overweight/obese subjects (p < 0.05 for both), and cholesterol absorption was reduced in both groups. However, relative and dietary cholesterol absorption were more effectively reduced in normal-weight subjects. In conclusion, overweight/obesity did not interfere with the serum cholesterol response to plant stanol ester consumption despite substantial differences in cholesterol metabolism between the groups.
  • Laivuori, Mirjami; Tolva, Johanna; Lokki, A. Inkeri; Linder, Nina; Lundin, Johan; Paakkanen, Riitta; Albäck, Anders; Venermo, Maarit; Mäyränpää, Mikko I.; Lokki, Marja-Liisa; Sinisalo, Juha (2020)
    Lamellar metaplastic bone, osteoid metaplasia (OM), is found in atherosclerotic plaques, especially in the femoral arteries. In the carotid arteries, OM has been documented to be associated with plaque stability. This study investigated the clinical impact of OM load in femoral artery plaques of patients with lower extremity artery disease (LEAD) by using a deep learning-based image analysis algorithm. Plaques from 90 patients undergoing endarterectomy of the common femoral artery were collected and analyzed. After decalcification and fixation, 4-μm-thick longitudinal sections were stained with hematoxylin and eosin, digitized, and uploaded as whole-slide images on a cloud-based platform. A deep learning-based image analysis algorithm was trained to analyze the area percentage of OM in whole-slide images. Clinical data were extracted from electronic patient records, and the association with OM was analyzed. Fifty-one (56.7%) sections had OM. Females with diabetes had a higher area percentage of OM than females without diabetes. In male patients, the area percentage of OM inversely correlated with toe pressure and was significantly associated with severe symptoms of LEAD including rest pain, ulcer, or gangrene. According to our results, OM is a typical feature of femoral artery plaques and can be quantified using a deep learning-based image analysis method. The association of OM load with clinical features of LEAD appears to differ between male and female patients, highlighting the need for a gender-specific approach in the study of the mechanisms of atherosclerotic disease. In addition, the role of plaque characteristics in the treatment of atherosclerotic lesions warrants further consideration in the future.
  • Ruuth, Maija; Lahelma, Mari; Luukkonen, Panu K.; Lorey, Martina B.; Qadri, Sami; Sädevirta, Sanja; Hyötyläinen, Tuulia; Kovanen, Petri T.; Hodson, Leanne; Yki-Järvinen, Hannele; Öörni, Katariina (2021)
    OBJECTIVE: We recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity. APPROACH AND RESULTS: The participants (36 subjects; age, 48±10 years; body mass index, 30.9±6.2 kg/m2) were randomized to consume an extra 1000 kcal/day of either unsaturated fat, saturated fat, or simple sugars (CARB) for 3 weeks. We measured plasma proatherogenic properties (susceptibility of LDL to aggregation, proteoglycan-binding, oxidized LDL) and concentrations and composition of plasma lipoproteins using nuclear magnetic resonance spectroscopy, and in LDL using liquid chromatography mass spectrometry, before and after the overfeeding diets. LDL aggregation increased in the saturated fat but not the other groups. This change was associated with increased sphingolipid and saturated triacylglycerols in LDL and in plasma and reduction of clusterin on LDL particles. Proteoglycan binding of plasma lipoproteins decreased in the unsaturated fat group relative to the baseline diet. Lipoprotein properties remained unchanged in the CARB group. CONCLUSIONS: The type of fat during 3 weeks of overfeeding is an important determinant of the characteristics and functional properties of plasma lipoproteins in humans.
  • Hernandez-Rios, Patricia; Pussinen, Pirkko J.; Vernal, Rolando; Hernandez, Marcela (2017)
    Oxidative stress is involved in the pathogenesis of a variety of inflammatory disorders. Apical periodontitis (AP) usually results in the formation of an osteolytic apical lesion (AL) caused by the immune response to endodontic infection. Reactive oxygen species (ROS) produced by phagocytic cells in response to bacterial challenge represent an important host defense mechanism, but disturbed redox balance results in tissue injury. This mini review focuses on the role of oxidative stress in the local and associated systemic events in chronic apical periodontitis. During endodontic infection, ligation of Toll-like receptors (TLRs) on phagocytes' surface triggers activation, phagocytosis, synthesis of ROS, activation of humoral and cellular responses, and production of inflammatory mediators, such as, cytokines and matrix metalloproteinases (MMPs). The increment in ROS perturbs the normal redox balance and shifts cells into a state of oxidative stress. ROS induce molecular damage and disturbed redox signaling, that result in the loss of bone homeostasis, increased pro-inflammatory mediators, and MMP overexpression and activation, leading to apical tissue breakdown. On the other hand, oxidative stress has been strongly involved in the pathogenesis of atherosclerosis, where a chronic inflammatory process develops in the arterial wall. Chronic AP is associated with an increased risk of cardiovascular diseases (CVD) and especially atherogenesis. The potential mechanisms linking these diseases are also discussed.
  • Ruuth, Maija; Äikäs, Lauri; Tigistu-Sahle, Feven; Käkelä, Reijo; Lindholm, Harri; Simonen, Piia; Kovanen, Petri T.; Gylling, Helena; Öörni, Katariina (2020)
    OBJECTIVE: Plant stanol ester supplementation (2-3 g plant stanols/d) reduces plasma LDL (low-density lipoprotein) cholesterol concentration by 9% to 12% and is, therefore, recommended as part of prevention and treatment of atherosclerotic cardiovascular disease. In addition to plasma LDL-cholesterol concentration, also qualitative properties of LDL particles can influence atherogenesis. However, the effect of plant stanol ester consumption on the proatherogenic properties of LDL has not been studied. APPROACH AND RESULTS: Study subjects (n=90) were randomized to consume either a plant stanol ester-enriched spread (3.0 g plant stanols/d) or the same spread without added plant stanol esters for 6 months. Blood samples were taken at baseline and after the intervention. The aggregation susceptibility of LDL particles was analyzed by inducing aggregation of isolated LDL and following aggregate formation. LDL lipidome was determined by mass spectrometry. Binding of serum lipoproteins to proteoglycans was measured using a microtiter well-based assay. LDL aggregation susceptibility was decreased in the plant stanol ester group, and the median aggregate size after incubation for 2 hours decreased from 1490 to 620 nm,P=0.001. Plant stanol ester-induced decrease in LDL aggregation was more extensive in participants having body mass index CONCLUSIONS: Consumption of plant stanol esters decreases the aggregation susceptibility of LDL particles by modifying LDL lipidome. The resulting improvement of LDL quality may be beneficial for cardiovascular health. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01315964. GRAPHIC ABSTRACT: A graphic abstract is available for this article.
  • Steffen, Hannah L. M.; Anderson, Josephine L. C.; Poot, Margot L.; Lei, Yu; Connelly, Margery A.; Bakker, Stephan J. L.; Öörni, Katariina; Tietge, Uwe J. F. (2021)
    Lipoprotein-proteoglycan binding is an early key event in atherosclerotic lesion formation and thus conceivably could play a major role in vasculopathy-driven chronic graft failure and cardiovascular mortality in renal transplant recipients. The present study investigated whether lipoproteinproteoglycan binding susceptibility (LPBS) of apoBcontaining lipoproteins and levels of the classical atherosclerosis biomarker LDL-C were associated with cardiovascular mortality (n = 130) and graft failure (n = 73) in 589 renal transplant recipients who were followed up from at least 1 year after transplantation for 9.5 years. At baseline, LPBS was significantly higher in patients who subsequently developed graft failure than in those with a surviving graft (1.68 +/- 0.93 vs. 1.46 +/- 0.49 nmol/mmol, P = 0.001). Cox regression analysis showed an association between LPBS and chronic graft failure in an age-and sex-adjusted model (hazard ratio: 1.45; 95% CI, 1.14-1.85; P = 0.002), but no association was observed with cardiovascular mortality. LDL-C levels were not associated with graft failure or cardiovascular mortality. This study shows that measurement of cholesterol retention outperformed the traditionally used quantitative parameter of LDL-C levels in predicting graft failure, suggesting a higher relevance of proatherogenic function than the quantity of apoBcontaining lipoproteins in chronic kidney graft failure.
  • Akhi, R.; Wang, C.; Nissinen, A. E.; Kankaanpaa, J.; Bloigu, R.; Paju, S.; Mantyla, P.; Buhlin, K.; Sinisalo, J.; Pussinen, P. J.; Horkko, S. (2019)
    A large body of literature has established the link between periodontal disease and cardiovascular disease. Oxidized low-density lipoproteins (OxLDLs) have a crucial role in atherosclerosis progression through initiation of immunological response. Monoclonal IgM antibodies to malondialdehyde-modified low-density lipoprotein (MDA-LDL) and to malondialdehyde acetaldehyde-modified low-density lipoprotein (MAA-LDL) have been shown to cross-react with the key virulence factors of periodontal pathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. We have previously shown that salivary IgA antibodies to MAA-LDL cross-react with P. gingivalis in healthy humans. In this study, we aim to assess whether oral mucosal immune response represented by salivary IgA to MAA-LDL and oral pathogens is associated with coronary artery disease (CAD). Also, the molecular mimicry through antibody cross-reaction between salivary IgA to MAA-LDL and oral pathogens was evaluated. The study subjects consisted of 451 patients who underwent a coronary angiography with no CAD (n = 133), stable CAD (n = 169), and acute coronary syndrome (ACS, n = 149). Elevated salivary IgA antibody levels to MAA-LDL, Rgp44 (gingipain A hemagglutinin domain of P. gingivalis), and Aa-HSP60 (heat shock protein 60 of A. actinomycetemcomitans) were discovered in stable-CAD and ACS patients when compared to no-CAD patients. In a multinomial regression model adjusted for known cardiovascular risk factors, stable CAD and ACS were associated with IgA to MAA-LDL (P = 0.016, P = 0.043), Rgp44 (P = 0.012, P = 0.004), Aa-HSP60 (P = 0.032, P = 0.030), Tannerella forsythia (P = 0.002, P = 0.004), Porphyromonas endodontalis (P = 0.016, P = 0.020), Prevotella intermedia (P = 0.038, P = 0.005), and with total IgA antibody concentration (P = 0.002, P = 0.016). Salivary IgA to MAA-LDL showed cross-reactivity with the oral pathogens tested in the study patients. The study highlights an association between salivary IgA to MAA-LDL and atherosclerosis. However, whether salivary IgA to MAA-LDL and the related oral humoral responses play a causal role in the development in the CAD should be elucidated in the future.
  • Nguyen, Su Duy; Öörni, Katariina; Lee-Rueckert, Miriam; Pihlajamaa, Tero; Metso, Jari; Jauhiainen, Matti; Kovanen, Petri T. (2012)
  • Judström, Ilona (Helsingfors universitet, 2009)
    In atherosclerosis, cholesterol accumulates in cholesterol-loaded macrophages (foam cells) forming cholesterol plaques in the arterial intima. Reverse cholesterol transport (RCT) is a mechanism in which HDL and its major structural protein apolipoprotein-A-1 (apoA-1) remove cholesterol from the foam cells and take it to the liver for its final excretion from the body in the faeces. An impaired removal of cholesterol from the foam cells is a potential contributor to a reduced RCT, which is related to a higher incidence of coronary heart disease. Chymase, a neutral protease of mast cells (MCs), is widely distributed in the connective tissue of most vertebrates and able to degrade apoA-1. After the degradation, HDL-particles are unable to interact with the ABCA-1 transporter protein on the surface of macrophages, which mediates efflux of cholesterol from the macrophage foam cells to HDL particles. It has been shown that chymase derived from rat peritoneal MCs is able to degrade apoA-1 even in the presence of blood plasma which contains natural inhibitors for chymase (α-2-macroglobulin and α-1-antichymotrypsin). In the present study we wanted to find out if mouse mast cell protease 4 (mMCP-4) isolated from peritoneal mast cells is able to maintain its enzymatic activity even in the presence of mouse serum and intraperitoneal fluid. A small molecular weight compound (S-2586) was used as a substrate. In the in vitro experiments a sonicated MC preparation that contains active chymase was used and the activity of chymase was measured in the presence of varying concentrations of plasma and intraperitoneal fluid. In the in vivo experiments we evaluate whether mast cell-dependent proteolysis of HDL particles does occur, and whether such modification inhibits their efficiency in inducing cellular cholesterol efflux in vitro. We found that both serum and intraperitoneal fluid inhibited chymase activity, serum to a higher extent. Systemic activation of MCs in mast cell-competent mice, but not in mast cell-deficient mice, in vivo led to a decreased ability of plasma and intraperitoneal fluid to act as cholesterol acceptors from cultured cholesterol-loaded macrophages. Local activation of peritoneal mast cells also blocked the cholesterol efflux-inducing effect of intraperitoneally injected human apoA-1. This work was performed at the Wihuri Research Institute. Licenses for animal work were approved by the Finnish Laboratory Animal Experiment Committee (Suomen eläinkoelautakunta, ELLA). Laboratory animals (female NMRI mice) were from the Viikki Laboratory Animal Centre of the University of Helsinki and the mast cell deficient strain of mice W-sash c-kit mutant KitW-sh/W-sh were from the Jackson Laboratory (BarHarbor, Maine). The work was supervised by the director of the Research Institute Petri Kovanen MD PhD and Miriam Lee-Rueckert PhD. Laboratory assistance was perceived from the technicians of the Wihuri Research Institute.
  • Lim, Nancy (Helsingin yliopisto, 2017)
    Background: Atherosclerosis is a common pathological process in arteries causing significant morbidity and mortality due to stroke and myocardial infarction. The progression of atherosclerosis is affected by both genes and external factors that interactively initiate and advance the pathological cascade. Heme oxygenase 1 (HO1) is a protein that degrades toxic heme and thereby plays a role in maintaining normal vascular function. The expression of the heme oxygenase 1 gene (HMOX1) is affected by a (GT)n polymorphism in its promoter area; short (GT)n alleles associate with higher HO1 expression in cell culture studies and are hypothesized to protect vessel wall from hemi-related oxidative damage. Objective: Our research group has previously found that patients that have suffered stroke due to atherosclerotic carotid stenosis show high expression of HMOX1 in their carotid plaques (CPs). The aim of this thesis was to investigate whether this finding is explained by the HMOX1 (GT)n promoter polymorphism, i.e. if the promoter polymorphism is associated to symptomatic carotid disease. Methods: HMOX1 promoter (GT)n polymorphism was genotyped in carotid stenosis patients (HeCES n=92) and population controls (Health 2000 Survey, n=964). HMOX1 mRNA and protein levels were measured from CPs by qRT-PCR and ELISA, respectively. Results: HMOX1 promoter (GT)n alleles in the Finnish population ranged between 20 and 40 repeats, where (GT)30 was the most common allele with a population frequency of 46.6%. When comparing carotid stenosis patients to controls, statistically significant association between a lack of short alleles (< (GT)30) and symptomatic carotid disease was not found (p=0.214). Whereas, carotid stenosis patients with an ulcerative plaque lacked significantly more often a short allele at the HMOX1 promoter variant (p=0.006). However, we did not find correlation between promoter genotypes and HMOX1 mRNA or protein levels in the CPs. Conclusions: Our results support the protective role of short HMOX1 promoter (GT)n variants against symptomatic carotid artery disease (CaD).