Omentin and subclinical cardiovascular disease in rheumatoid arthritis

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Masters of Science in Medicine. Johannesburg, 2016The enhanced cardiovascular disease (CVD) risk experienced by patients with rheumatoid arthritis (RA) remains largely unexplained. Traditional risk factors including hypertension, dyslipidemia, diabetes, smoking and altered adiposity states do not fully account for the increased CVD risk in RA. High grade systemic inflammation, as characteristically present in patients with RA, is associated with adverse metabolic risk factor profiles and can directly increase atherogenesis. Further, genetic polymorphisms are related to CVD in RA. Notably, the impact of cardiovascular risk factors on CVD is epidemiological health transition stage dependent within populations. Indeed, cardiovascular risk factor-CVD relations consistently differ amongst patients with RA from developed compared to developing populations. In line with these findings, adequate CVD risk stratification in RA currently eludes us. Adipose tissue derived adipokines are major determinants of systemic metabolism. Several recent studies revealed that adipokines are involved in RA activity and severity. Adipokines play key roles in interactions between obesity, metabolic cardiovascular risk factors and systemic inflammation, all of which contribute to cardiovascular pathology. These adipokine effects depend on pathophysiological context. Against this background, in the present study, we investigated the associations of omentin concentrations with subclinical CVD and whether population origin and RA activity and severity impacts on the respective relationships. Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of 6 endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate plaque stability, were identified in multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels (β=-364 (0.113), p=0.002). This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate (ESR) and joint deformity count (interaction p value=0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, in stratified analysis, the omentin-MMP-3 concentration relationship was reproduced in white (β (SE)=- 0.450 (0.153), p=0.0004) but not black patients (β (SE)=- 0.099 (0.195), p=0.6), in participants with disease remission or mild disease activity (β (SE)=-0.411 (0.139), p=0.004) but not with moderate or severe RA activity (β (SE)=-0.286 (0.202), p=0.2), and in those with a small (β (SE)=-0.534 (0.161), p=0.001) but not large erythrocyte sedimentation rate (ESR) (-0.212 (0.168), p=0.2) and without (β (SE)=-0.554 (0.165), p=0.0001) but not with large joint deformity counts (-0.110 (0.173), p=0.5). Omentin levels were unrelated to endothelial activation and atherosclerosis. Omentin concentrations do not represent endothelial activation and atherosclerosis extent in RA. However, omentin concentrations were inversely associated with those of MMP-3, a surrogate marker of plaque vulnerability to rupture, in white but not black Africans with RA. This inverse relationship was also absent RA patients with moderate or severe RA activity and large ESR values and joint deformity counts. A loss of beneficial effects of omentin on plaque instability may contribute to the link between severe disease and increased cardiovascular risk in RA.MT201

Nové biomarkery u pacientů s onemocněním ledvin

Chronické onemocnění ledvin a akutní poškození ledvin patří mezi významné zdravotní problémy v populaci. Je důležité, abychom byli schopni rozpoznat osoby s vysokým rizikem nepříznivého vývoje zdravotního stavu, progresí onemocnění a přidružených kardiovaskulárních komplikací. Cílem disertační práce bylo studium nových perspektivních biomarkerů, jejich vztah k renální funkci, chronickému zánětu, případně zvýšenému kardiovaskulárnímu riziku. Studovány byly: placentární růstový faktor (PlGF), s těhotenstvím asociovaný protein A (PAPP-A), matrixová metalloproteináza 2 (MMP-2), matrixová metalloproteináza 9 (MMP-9), solubilní receptor pro konečné produkty pokročilé glykace (sRAGE), protein vázající vápník S100A12 - nově identifikovaný extracelulární protein vázající se na receptor pro konečné produkty pokročilé glykace (EN-RAGE) a amfoterin (HMGB-1) u pacientů se sníženou funkcí ledvin včetně pacientů s chronickým renálním onemocněním, hemodialyzovaných, pacientů s akutním poškozením ledvin a zdravých kontrol pro srovnání. První studie odhalila, že hladina PlGF je zvýšená u pacientů se sníženou funkcí ledvin. Druhá studie zjistila spojitost hladin MMP-2 a PAPP-A s proteinurií u pacientů s chronickým renálním onemocněním. Sérové hladiny MMP-2, MMP-9 a PAPP-A se výrazně lišily u pacientů s různými nefropatiemi....Chronic kidney disease (CKD) and acute kidney injury (AKI) are major public health problems. It is important to be able to identify those at high risk of adverse outcome, CKD progression and associated cardiovascular disease. The aim of the thesis was to study novel promising biomarkers, their relationship to kidney function, chronic inflammation and/or cardiovascular risk - placental growth factor (PlGF), pregnancy associated plasma protein A (PAPP-A), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), soluble receptor for advanced glycation end products (sRAGE), calcium binding protein S100A12 or extracellular newly identified RAGE binding protein (EN-RAGE), and high mobility group box protein-1 (HMGB-1) in patients with renal diseases including CKD, haemodialysis (HD), AKI patients, and healthy controls for comparison. First study revealed that PlGF is elevated in patients with decreased renal function. Second study demonstrated the association of MMP-2 and PAPP-A with proteinuria in patients with CKD. Moreover, serum MMP-2, MMP-9 and PAPP-A levels significantly differed in patients with various nephropathies. EN-RAGE levels are not elevated in patients with CKD, but are related to inflammatory status. PAPP-A, EN-RAGE and HMGB-1 levels are significantly elevated, but sRAGE and PlGF...Ústav lékařské biochemie a laboratorní diagnostiky 1. LF UK a VFNInstitute of Medical Biochemistry and Laboratory Medicine First Faculty of MedicineFirst Faculty of Medicine1. lékařská fakult

Ethnic differences in endothelial function and monocyte subsets in heart failure

Introduction and Aims: The progressive nature of heart failure (HF) is reflected by its complex pathophysiology, featured by imbalance of damaging and reparative factors. The overall aim was to assess the implication of endothelial (dys)function, monocyte subsets, different types of endothelial progenitors and plasma microparticles in subjects with HF. A special focus was an investigation of possible ethnic differences in these parameters. Methods: Parameters of vascular function, monocyte subsets, endothelial progenitors, and cellular microparticles were compared between South Asian subjects with systolic HF, and those with heart disease without HF and healthy controls. Ethnic differences in HF were assessed in three ethnic groups: South Asians, Whites, and African-Caribbeans. Additionally, leukocyte counts were compared between subjects with HF with reduced or preserved ejection fraction, whose outcome (mortality) was recorded during follow-up. Results: South Asian subjects with HF had significantly impaired micro- and macrovascular endothelial function, reduced levels of endothelial progenitors, and monocytes with reparative potential, but increased levels of microparticles. In HF patients, a high count of monocyte microparticles was associated with low ejection fraction. There were significant ethnic differences in characteristics of microvascular endothelial function, counts of CD14++CD16+ and CD14+CD16++ monocytes and monocyte-derived endothelial progenitors. On multivariate analysis, a high monocyte count was a significant predictor of death in HF with preserved ejection fraction unlike in those with systolic HF. Conclusions: Significant impairment of microvascular endothelial function is present in South Asian subjects with HF. High monocyte count is an independent predictor of death in HF with preserved ejection fraction. The value of the tested biological markers as therapeutic targets should be explored in future studies

Angiogenesis in Adipose Tissue: How can Moderate Caloric Restriction Affects Obesity-Related Endothelial Dysfunction?

The plasticity of adipose tissue (AT) is related to its angiogenic ability. Angiogenesis is a multistep process which involves endothelial cell (EC) proliferation, migration, invasion and finally tube formation. AT as a secretory organ produces adipokines, which contributes to the development of subclinical inflammation. The inflammation-related adipokines deteriorate EC function and in consequence change the production of endothelial mediators responsible for vascular homeostasis and angiogenesis, leading to cardiovascular diseases (CVD) in obese patients. Additionally, the recent observation suggests that AT is poorly oxygenated in obesity. Hypoxia limits the healthy expansion of AT and stimulates a molecular response, enhancing nuclear factor kappa-B (NF-kB) and hypoxia-inducible factor (HIF-1) expression. HIF-1α induction does not start a normal angiogenic process but rather induces inflammatory response and fibrosis that is strongly associated with insulin resistance (IR). It is believed that EC dysfunction in obesity can be reduced by caloric restriction (CR). Moderate CR reflects a real-life situation and could be optimal to achieve an EC improvement. It reduces adiposity leading to pro-angiogenic, anti-inflammatory and—to a lesser extent—anti-oxidative cellular effects, which not only preserves the healthy EC phenotype but also leads to an improvement of AT remodeling and prevent systemic IR

Effects of physical exercise on inflammatory markers of atherosclerosis.

It is well established that physically fit individuals have a reduced risk of developing CVD (cardiovascular disease) and other age-related chronic disorders. Regular exercise is an established therapeutic intervention with an enormous range of benefits. Chronic low-grade systemic inflammation may be involved in atherosclerosis, diabetes and in pathogenesis of several chronic pathological conditions; recent findings confirm that physical activity induces an increase in the systemic levels of a number of cytokines and chemokines with anti-inflammatory properties. The possibility that regular physical exercise exerts anti-inflammation activity, being the interaction between contracting muscle and the other tissues and the circulating cells mediated through signals transmitted by "myokines" produced with muscle contractions. To date the list of myokines includes IL-6, IL-8, and IL-15. During muscle contractions are also released IL-1 receptor antagonis and sTNF-R, molecules that contribute to provide anti-inflammatory actions. Nevertheless discrepancies, analysis of available researches seem to confirm the efficacy of regular physical training as a nonpharmacological therapy having target chronic low-grade inflammation. Given this, physical exercise could be considerate a useful weapon against local vascular and systemic inflammation in atherosclerosis. Several mechanisms explain the positive effect of chronic exercise, nevertheless, these mechanisms do not fully enlighten all pathways by which exercise can decrease inflammation and endothelial dysfunction, and hence modulate the progression of the underlying disease progres

Influence of homocysteine on the interaction between circulating monocytes and endothelial cells

Mild hyperhomocysteinemia is an independent risk factor for the development of coronary artery disease, cerebrovascular disease and peripheral arterial disease. The mechanisms by which hyperhomocysteinemia promotes vascular disease are not completely understood yet. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine’s deleterious effects on the vasculature. Elevated levels of homocysteine lead to increased generation of superoxide anion in endothelial cells by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation rate of homocysteine and other aminothiols in the circulation. Furthermore, homocysteine has been shown to inhibit the activity of important cellular antioxidant enzymes, like the cellular isoform of glutathione peroxidase or superoxide dismutase, which may contribute to homocysteine’s induced oxidant stress. The resulting increase in reactive oxygen species leads to decreased bioavailability of the endothelium-derived signaling molecule nitric oxide via oxidative inactivation and thereby induces endothelial dysfunction. This seems to play a central role in the molecular mechanisms underlying the effects of homocysteine on vascular function. Hyperhomocysteinemia not only leads to endothelial dysfunction but also promotes the development and propagation of atherosclerotic lesion in atherosclerosis-prone animal models. As the recruitment of circulating monocytes to the vessel wall plays a crucial role in the process of atherosclerosis, the purpose of this study was to examine the influence of homocysteine on the interaction of endothelial cells with monocytes. Exposure of endothelial monolayers to D,L- and L-homocysteine resulted in a time- and dose-dependent increase in adherent THP-1 cells by upregulating ICAM-1 expression on endothelial cells. L-cysteine and D-homocysteine had no effects. This indicates that the stimulatory effect is specific for the naturally occurring L-stereoisomer and rather a biochemical than a chemical effect. The increased endothelial expression of ICAM-1 seems to be mediated by increased activation of the nuclear transcription factor NF-kB, as shown by increased nuclear translocation of NF-kB in homocysteine-incubated endothelial cells. In accordance, inhibition of NF-kB translocation by a synthetic inhibitor Bay 11-7082 significantly diminished homocysteine-induced ICAM-1 expression and adhesion of monocytes to endothelial cells. In addition, incubation of monocytes with D,L- homocysteine and L-homocysteine resulted in significant increase in the number of adhering monocytes to unstimulated endothelial monolayer by upregulating the expression of beta-2 integrins. Furthermore, homocysteine-incubation of endothelial cells and monocytes resulted in a dose-dependent and significant increase in the intracellular generation of reactive oxygen species. In support of the role of increased oxidant stress for the above mentioned effects, treatment of endothelial cells with the superoxide scavengers MnTBAP or Tiron together with homocysteine abolished homocysteine-induced monocyte adhesion, ICAM-1 expression and the nuclear translocation of NF-kB. Incubation of THP-1 monocytes with Tiron abolished homocysteine-induced beta-2 integrin expression on these cells and adhesion to unstimulated endothelial cells. These findings suggest that superoxide anion radicals mediate homocysteine’s effects on endothelium-monocyte interactions. In addition to previous studies that indicated that a significant source of reactive oxygen species in homocysteine-treated endothelial cells might be endothelial nitric oxide synthase, experiments using inhibitors of nitric oxide synthase in THP-1 cells indicated that nitric oxide synthase-dependent generation of superoxide anion also occurs in homocysteine-incubated THP-1 cells. This mechanism may contribute to homocysteine-induced oxidant stress. The information generated from these studies may be helpful in designing intervention strategies aimed at inhibiting the generation of reactive oxygen species in the vasculature that is associated with signaling events of monocyte recruitment and infiltration involved in atherosclerosis

Lipid distress-syndrome and prospects of its correction by statines

Endothelial dysfunction in peritonitis: The formed concept of lipid distress syndrome (LDS) allows us to develop a working hypothesis on the key role of endothelial dysfunction in the aggressive development of atherosclerosis. The role of vascular endothelium in atherosclerosis: The process of NO production from L-arginine through eNOS involving tetrahydrobiopterin (BH4) is discussed. With the degradation of BH4 along the free radical path, an "eNOS uncouplation" (uncoupled eNOS). The clinical role of statins: Statins manifests itself by inhibiting the enzyme 3-hydroxy- 3-methylglutaryl-coenzyme A (HMG-CoA reductase). Many large, randomized clinical trials have shown that lipid-lowering strategies that include statins have an anti-atherogenic potentia

A dissection of SARS‑CoV2 with clinical implications (Review)

We are being confronted with the most consequential pandemic since the Spanish flu of 1918‑1920 to the extent that never before have 4 billion people quarantined simultaneously; to address this global challenge we bring to the forefront the options for medical treatment and summarize SARS‑CoV2 structure and functions, immune responses and known treatments. Based on literature and our own experience we propose new interventions, including the use of amiodarone, simvastatin, pioglitazone and curcumin. In mild infections (sore throat, cough) we advocate prompt local treatment for the naso‑pharynx (inhalations; aerosols; nebulizers); for moderate to severe infections we propose a tried‑and‑true treatment: the combination of arginine and ascorbate, administered orally or intravenously. The material is organized in three sections: i) Clinical aspects of COVID‑19; acute respiratory distress syndrome (ARDS); known treatments; ii) Structure and functions of SARS‑CoV2 and proposed antiviral drugs; iii) The combination of arginine‑ascorbate