The role of connexin 37 gene polymorphism (1019C > T; Pro319Ser) in cardiovascular disease

In spite of the strong prognostic value of all traditional cardiovascularrisk factors, still striking differences exist in the prevalence of clinical events between patients at apparently similar risk. One of the main reasons is different genetic background. One of recently discussed candidate genes for cardiovascular disease is the gene for the protein Connexin 37 (Cx37). This protein is a part of gap junctions responsible for communications between cells including cells in the vessel wall. Studies focused on the association between Cx37 gene polymorphism (1019C > T; Pro319Ser) and cardiovascular disease demonstrate inconsistent results. Our findings in 1.316 men and women indicated that the Cx37 gene polymorphism (genotype CC) is significantly associated with acute coronary syndrome in non-smoking women. In addition, in urban and rural women from general population (n = 1.056) with impaired fasting glycaemia the same genotype is associated with increased intima media thickness of carotid arteries measured by ultrasound. Finally, in 289 women with diabetestype 1 or 2, and in 208 women from general population with central obesity, the CC genotype was associated with lower ankle brachial blood pressure index. These data indicate that Cx37 gene polymorphism could have gender- and smoking-dependent effects on acute coronary events and glucose dependent effect on atherosclerosis in women. Keywords: connexin 37 gene polymorphism, atherosclerosis, acute coronary syndromes, women smoking, glycaemia.Незважаючи на однозначність прогностичного значення усіх традиційних факторів ризику серцево-судинних захворювань, існують значні розбіжності у їхніх клінічних проявах у різних пацієнтів. Однією з основних причин цього є неоднаковий генетичний фон. З-поміж недавно обговорюваних генів-кандидатів, які впливають на серцево-судинні захворювання, обрано ген білка конексину 37 (Cx37). Цей білок відповідає за міжклітинні взаємодії, включаючи клітини стінок кровоносних судин. Дослідження, зосереджені на пошуку зв’язку між поліморфізмом гена конексину 37 (1019C > T; Pro319Ser) та серце - во-судинними захворюваннями, показують суперечливі результати. Наші дослідження 1316 чоловіків і жінок демонструють, що поліморфізм гена Сх37 (генотип СС) значною мірою пов’язаний з гострим коронарним синдромом у жінок, які не курять. Окрім того, у міських і сільських жінок із загальної популяції (n = 1056) з порушеною глікемією цей же генотип пов’язаний із збільшенням товщини інтими сонних артерій, виміряної ультразвуком. У 289 жінок з діабетом 1-го або 2-го типу і у 208 жінок із загальної популяції з ожирінням генотип СС виявився зв’язаним з нижчим щиколотко-плечовим індексом тиску крові. Такі дані показують, що стать і куріння діють на гострі коронарні прояви, обумовлені поліморфізмом гена Cx37, для жінок виявлено також глюкозозалежний вплив на атеросклероз. Ключові слова: поліморфізм гена конексину 37, атеросклероз, гострий коронарний синдром, куріння жінок, глікемія.Несмотря на однозначность прогностического значения всех традиционных факторов риска сердечно-сосудистых заболеваний, по-прежнему существуют значительные отличия в их клинических проявлениях у разных пациентов. Одной из основных причин этого является неодинаковый генетический фон. Среди недавно обсуждаемых генов-кандидатов, влияющих на сердечно-сосудистые заболевания, выбран ген белка коннексина 37 (Cx37). Этот белок ответствен за межклеточные взаимодействия, включая клетки стенок кровеносных сосудов. Исследования, сосредоточенные на поисках связи между Cx37 полиморфизмом гена (1019C > T; Pro319Ser) и сердечно-сосудистыми заболеваниями, показывают противоречивые результаты. Наши исследования 1316 мужчин и женщин демонстрируют, что полиморфизм гена Cx37 (генотип СС) в значительной степени связан с острым коронарным синдромом у некурящих женщин. Кроме того, у городских и сельских женщин из общей популяции (n = 1056) с нарушенной гликемией тот же генотип связан с увеличением толщины интимы сонных артерий, измеренной ультразвуком. У 289 женщин с диабетом 1-го или 2-го типа и у 208 женщин из общей популяции с ожирением генотип СС оказался связанным с более низким лодыжечно-плечевым индексом давления крови. Эти данные показывают, что пол и курение действуют на острые коронарные проявления, обусловленные полиморфизмом гена Cx37, для женщин выявлен также глюкозозависимое влияние на атеросклероз. Ключевые слова: полиморфизма гена коннексина 37, атеросклероз, острый коронарный синдром, курение женщин, гликемия

Traditional Risk Factors of Acute Coronary Syndrome in Four Different Male Populations – Total Cholesterol Value Does Not Seem To Be Relevant Risk Factor

Cardiovascular diseases are the most common cause of mortality and morbidity in most populations. As the traditional modifiable risk factors (smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity) were defined decades ago, we decided to analyze recent data in patients who survived acute coronary syndrome (ACS). The Czech part of the study included data from 999 males, and compared them with the post-MONICA study(1,259 males, representing general population). The Lithuanianstudy included 479 male patients and 456 age-matched controls. The Kazakhstan part included 232 patients and 413 controls.In two countries, the most robust ACS risk factor was smoking (OR 3.85 in the Czech study and 5.76 in the Lithuanian study), followed by diabetes (OR 2.26 and 2.07) and hypertension (moderate risk elevation with OR 1.43 and 1.49). These factors did not influence the ACS risk in Kazakhstan. BMI had no significant effect on ACS and plasma cholesterol was surprisingly significantly lower (P<0.001) in patients than in controls in all countries (4.80±1.11 vs. 5.76±1.06 mmol/l in Czechs; 5.32±1.32 vs. 5.71±1.08 mmol/l in Lithuanians; 4.88±1.05 vs. 5.38±1.13 mmol/l in Kazakhs/Russians). Results from our study indicate substantial heterogeneity regarding major CVD risk factors in different populations with the exception of plasma total cholesterol which was inversely associated with ACS risk in all involved groups. These data reflect ethnical and geographical differences as well as changing pattern of cardiovascular risk profiles

LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF

Toll–IL-1–resistance (TIR) domain–containing adaptor-inducing IFN-β (TRIF)–related adaptor molecule (TRAM) is the fourth TIR domain–containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-κB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-α/β, regulated on activation, normal T cell expressed and secreted (RANTES), and γ interferon–inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the function of TRAM is restricted to the TLR4 pathway. TRAM interacts with TRIF, MyD88 adaptor–like protein (Mal)/TIRAP, and TLR4 but not with TLR3. These studies suggest that TRIF and TRAM both function in LPS-TLR4 signaling to regulate the MyD88-independent pathway during the innate immune response to LPS

International Union of Angiology (IUA) consensus paper on imaging strategies in atherosclerotic carotid artery imaging: From basic strategies to advanced approaches

Cardiovascular disease (CVD) is the leading cause of mortality and disability in developed countries. According to WHO, an estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths. Of these deaths, 85% were due to major adverse cardiac and cerebral events. Early detection and care for individuals at high risk could save lives, alleviate suffering, and diminish economic burden associated with these diseases. Carotid artery disease is not only a well-established risk factor for ischemic stroke, contributing to 10%–20% of strokes or transient ischemic attacks (TIAs), but it is also a surrogate marker of generalized atherosclerosis and a predictor of cardiovascular events. In addition to diligent history, physical examination, and laboratory detection of metabolic abnormalities leading to vascular changes, imaging of carotid arteries adds very important information in assessing stroke and overall cardiovascular risk. Spanning from carotid intima-media thickness (IMT) measurements in arteriopathy to plaque burden, morphology and biology in more advanced disease, imaging of carotid arteries could help not only in stroke prevention but also in ameliorating cardiovascular events in other territories (e.g. in the coronary arteries). While ultrasound is the most widely available and affordable imaging methods, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), their combination and other more sophisticated methods have introduced novel concepts in detection of carotid plaque characteristics and risk assessment of stroke and other cardiovascular events. However, in addition to robust progress in usage of these methods, all of them have limitations which should be taken into account. The main purpose of this consensus document is to discuss pros but also cons in clinical, epidemiological and research use of all these techniques

Interferon-Alpha Mediates Restriction of Human Immunodeficiency Virus Type-1 Replication in Primary Human Macrophages at an Early Stage of Replication

Type I interferons (IFNα and β) are induced directly in response to viral infection, resulting in an antiviral state for the cell. In vitro studies have shown that IFNα is a potent inhibitor of viral replication; however, its role in HIV-1 infection is incompletely understood. In this study we describe the ability of IFNα to restrict HIV-1 infection in primary human macrophages in contrast to peripheral blood mononuclear cells and monocyte-derived dendritic cells. Inhibition to HIV-1 replication in cells pretreated with IFNα occurred at an early stage in the virus life cycle. Late viral events such as budding and subsequent rounds of infection were not affected by IFNα treatment. Analysis of early and late HIV-1 reverse transcripts and integrated proviral DNA confirmed an early post entry role for IFNα. First strand cDNA synthesis was slightly reduced but late and integrated products were severely depleted, suggesting that initiation or the nucleic acid intermediates of reverse transcription are targeted. The depletion of integrated provirus is disproportionally greater than that of viral cDNA synthesis suggesting the possibility of a least an additional later target. A role for either cellular protein APOBEC3G or tetherin in this IFNα mediated restriction has been excluded. Vpu, previously shown by others to rescue a viral budding restriction by tetherin, could not overcome this IFNα induced effect. Determining both the viral determinants and cellular proteins involved may lead to novel therapeutic approaches. Our results add to the understanding of HIV-1 restriction by IFNα

Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection

The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression

Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection

The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression

The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer

INTRODUCTION: ISG15 is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. However, alterations in the ISG15 signalling pathway have also been found in several human tumour entities. To the best of our knowledge, in the current study we present for the first time a systematic characterisation of ISG15 expression in human breast cancer and normal breast tissue both at the mRNA and protein level. METHOD: Using semiquantitative real-time PCR, cDNA dot-blot hybridisation and immunohistochemistry, we systematically analysed ISG15 expression in invasive breast carcinomas (n = 910) and normal breast tissues (n = 135). ISG15 protein expression was analysed in two independent cohorts on tissue microarrays; in an initial evaluation set of 179 breast carcinomas and 51 normal breast tissues; and in a second large validation set of 646 breast carcinomas and 10 normal breast tissues. In addition, a collection of benign and malignant mammary cell lines (n = 9) were investigated for ISG15 expression. RESULTS: ISG15 was overexpressed in breast carcinoma cells compared with normal breast tissue, both at the RNA and protein level. Recurrence-free (p = 0.030), event-free (p = 0.001) and overall (p = 0.001) survival analyses showed a significant correlation between ISG15 overexpression and unfavourable prognosis. CONCLUSION: Therefore, ISG15 may represent a novel breast tumour marker with prognostic significance and may be helpful in selecting patients for and predicting response to the treatment of human breast cancer

Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers

Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible, nuclear proteins, associated with both, infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, we and others have previously demonstrated a high frequency of AIM2-alterations in microsatellite unstable (MSI-H) tumors. To further elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive target genes by microarray based gene expression profiling of 22 244 human genes. A total of 111 transcripts were significantly upregulated, whereas 80 transcripts turned out to be significantly downregulated in HCT116 cells, constitutively expressing AIM2, compared with AIM2-negative cells. Among the upregulated genes that were validated by quantitative PCR and western blotting we recognized several interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA), as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in 10 different IFN-γ treated colorectal cancer cell lines. Moreover, small interfering RNA-mediated knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB and CIITA in IFN-γ-treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon doxycyclin-regulated transient induction of AIM2. Luciferase reporter assays revealed induction of the HLA-DR promoter upon AIM2 transfection in different cell lines. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autostimulating manner. Our data indicate that AIM2 mediates both IFN-γ dependent and independent induction of several ISGs, including genes encoding the major histocompatibility complex (MHC) class II antigens HLA-DR-α and -β. This suggests a novel role of the IFN/AIM2/ISG cascade likewise in cancer cells