scholarly journals Omacor Protects Normotensive and Hypertensive Rats Exposed to Continuous Light from Increased Risk to Malignant Cardiac Arrhythmias

Marine Drugs ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. 659
Author(s):  
Tamara Egan Benova ◽  
Csilla Viczenczova ◽  
Barbara Szeiffova Bacova ◽  
Jitka Zurmanova ◽  
Vladimir Knezl ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Electrical Coupling ◽  
Continuous Light ◽  
Male Rat ◽  
Human Populations ◽  
Omega 3 ◽  
Spontaneously Hypertensive ◽  
Protein Levels ◽  
Populations At Risk ◽  
Increased Risk

Light pollution disturbs circadian rhythm, and this can also be deleterious to the heart by increased susceptibility to arrhythmias. Herein, we investigated if rats exposed to continuous light had altered myocardial gene transcripts and/or protein expression which affects arrhythmogenesis. We then assessed if Omacor® supplementation benefitted affected rats. Male and female spontaneously hypertensive (SHR) and normotensive Wistar rats (WR) were housed under standard 12 h/12 h light/dark cycles or exposed to 6-weeks continuous 300 lux light for 24 h. Half the rats were then treated with 200 mg/100 g b.w. Omacor®. Continuous light resulted in higher male rat vulnerability to malignant ventricular fibrillation (VF). This was linked with myocardial connexin-43 (Cx43) down-regulation and deteriorated intercellular electrical coupling, due in part to increased pro-inflammatory NF-κB and iNOS transcripts and decreased sarcoplasmic reticulum Ca2+ATPase transcripts. Omacor® treatment increased the electrical threshold to induce the VF linked with amelioration of myocardial Cx43 mRNA and Cx43 protein levels and the suppression of NF-κB and iNOS. This indicates that rat exposure to continuous light results in deleterious cardiac alterations jeopardizing intercellular Cx43 channel-mediated electrical communication, thereby increasing the risk of malignant arrhythmias. The adverse effects were attenuated by treatment with Omacor®, thus supporting its potential benefit and the relevance of monitoring omega-3 index in human populations at risk.

scholarly journals Antiarrhythmic Effects of Melatonin and Omega-3 Are Linked with Protection of Myocardial Cx43 Topology and Suppression of Fibrosis in Catecholamine Stressed Normotensive and Hypertensive Rats

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 546 ◽  
Author(s):  
Barbara Szeiffova Bacova ◽  
Csilla Viczenczova ◽  
Katarina Andelova ◽  
Matus Sykora ◽  
Kiranj Chaudagar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Connexin 43 ◽  
Electrical Coupling ◽  
Threshold Current ◽  
Prolonged Treatment ◽  
Diffuse Fibrosis ◽  
Omega 3 ◽  
Hypertensive Rats ◽  
Protein Levels ◽  
Coupling Protein

Cardiac β-adrenergic overstimulation results in oxidative stress, hypertrophy, ischemia, lesion, and fibrosis rendering the heart vulnerable to malignant arrhythmias. We aimed to explore the anti-arrhythmic efficacy of the anti-oxidative and anti-inflammatory compounds, melatonin, and omega-3, and their mechanisms of actions in normotensive and hypertensive rats exposed to isoproterenol (ISO) induced β-adrenergic overdrive. Eight-month-old, male SHR, and Wistar rats were injected during 7 days with ISO (cumulative dose, 118 mg/kg). ISO rats were either untreated or concomitantly treated with melatonin (10 mg/kg/day) or omega-3 (Omacor, 1.68 g/kg/day) until 60 days of ISO withdrawal and compared to non-ISO controls. Findings showed that both melatonin and omega-3 increased threshold current to induce ventricular fibrillation (VF) in ISO rats regardless of the strain. Prolonged treatment with these compounds resulted in significant suppression of ISO-induced extracellular matrix alterations, as indicated by reduced areas of diffuse fibrosis and decline of hydroxyproline, collagen-1, SMAD2/3, and TGF-β1 protein levels. Importantly, the highly pro-arrhythmic ISO-induced disordered cardiomyocyte distribution of electrical coupling protein, connexin-43 (Cx43), and its remodeling (lateralization) were significantly attenuated by melatonin and omega-3 in Wistar as well as SHR hearts. In parallel, both compounds prevented the post-ISO-related increase in Cx43 variant phosphorylated at serine 368 along with PKCε, which are known to modulate Cx43 remodeling. Melatonin and omega-3 increased SOD1 or SOD2 protein levels in ISO-exposed rats of both strains. Altogether, the results indicate that anti-arrhythmic effects of melatonin and omega-3 might be attributed to the protection of myocardial Cx43 topology and suppression of fibrosis in the setting of oxidative stress induced by catecholamine overdrive in normotensive and hypertensive rats.

Myocardial NOS activity and connexin-43 expression in untreated and omega-3 fatty acids-treated spontaneously hypertensive and hereditary hypertriglyceridemic rats

2010 ◽  
Vol 347 (1-2) ◽  
pp. 163-173 ◽  
Author(s):  
Jana Radosinska ◽  
Barbara Bacova ◽  
Iveta Bernatova ◽  
Jana Navarova ◽  
Anna Zhukovska ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Connexin 43 ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Spontaneously Hypertensive

Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythmias

2013 ◽  
Vol 91 (8) ◽  
pp. 633-639 ◽  
Author(s):  
Tamara Benova ◽  
Csilla Viczenczova ◽  
Jana Radosinska ◽  
Barbara Bacova ◽  
Vladimir Knezl ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Wistar Rats ◽  
Electrical Coupling ◽  
Wistar Rat ◽  
Spontaneously Hypertensive ◽  
Kinase C ◽  
Rat Hearts ◽  
Cx43 Mrna ◽  
Cardioprotective Effects ◽  
Coupling Protein

We hypothesized that the pineal hormone melatonin, which exhibits cardioprotective effects, might affect myocardial expression of cell-to-cell electrical coupling protein connexin-43 (Cx43) and protein kinase C (PKC) signaling, and hence, the propensity of the heart to lethal ventricular fibrillation (VF). Spontaneously hypertensive (SHR) and normotensive Wistar rats fed a standard rat chow received melatonin (40 μg/mL in drinking water during the night) for 5 weeks, and were compared with untreated rats. Melatonin significantly reduced blood pressure and normalized triglycerides in SHR, whereas it decreased body mass and adiposity in Wistar rats. Compared with healthy rats, the threshold to induce sustained VF was significantly lower in SHR (18.3 ± 2.6 compared with 29.2 ± 5 mA; p < 0.05) and increased in melatonin-treated SHR and Wistar rats to 33.0 ± 4 and 32.5 ± 4 mA. Melatonin attenuated abnormal myocardial Cx43 distribution in SHR, and upregulated Cx43 mRNA, total Cx43 protein, and its functional phosphorylated forms in SHR, and to a lesser extent, in Wistar rat hearts. Moreover, melatonin suppressed myocardial proapoptotic PKCδ expression and increased cardioprotective PKCε expression in both SHR and Wistar rats. Our findings indicate that melatonin protects against lethal arrhythmias at least in part via upregulation of myocardial Cx43 and modulation of PKC-related cardioprotective signaling.

scholarly journals Cardiac Connexin-43 and PKC Signaling in Rats With Altered Thyroid Status Without and With Omega-3 Fatty Acids Intake

2016 ◽  
pp. S77-S90 ◽  
Author(s):  
B. SZEIFFOVÁ BAČOVÁ ◽  
T. EGAN BEŇOVÁ ◽  
C. VICZENCZOVÁ ◽  
T. SOUKUP ◽  
H. RAUCHOVÁ ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Thyroid Hormones ◽  
Connexin 43 ◽  
Heart Function ◽  
Electrical Coupling ◽  
Omega 3 ◽  
Thyroid Status ◽  
Pkc Epsilon ◽  
Coupling Protein ◽  
Altered Thyroid

Thyroid hormones are powerful modulators of heart function and susceptibility to arrhythmias via both genomic and non-genomic actions. We aimed to explore expression of electrical coupling protein connexin-43 (Cx43) in the heart of rats with altered thyroid status and impact of omega-3 polyunsaturated fatty acids (omega-3) supplementation. Adult male Lewis rats were divided into following six groups: euthyroid controls, hyperthyroid (treated with T3) and hypothyroid (treated with methimazol) with or without six-weeks lasting supplementation with omega-3 (20 mg/100 g/day). Left and right ventricles, septum and atria were used for immunoblotting of Cx43 and protein kinase C (PKC). Total expression of Cx43 and its phosphorylated forms were significantly increased in all heart regions of hypothyroid rats compared to euthyroid controls. In contrast, the total levels of Cx43 and its functional phosphorylated forms were decreased in atria and left ventricle of hyperthyroid rats. In parallel, the expression of PKC epsilon that phosphorylates Cx43, at serine 368, was increased in hypothyroid but decreased in hyperthyroid rat hearts. Omega-3 intake did not significantly affect either Cx43 or PKC epsilon alterations. In conclusion, there is an inverse relationship between expression of cardiac Cx43 and the levels of circulating thyroid hormones. It appears that increased propensity of hyperthyroid while decreased of hypothyroid individuals to malignant arrhythmias may be in part attributed to the changes in myocardial Cx43.

scholarly journals Suppression of β1-Adrenoceptor Autoantibodies is Involved in the Antiarrhythmic Effects of Omega-3 Fatty Acids in Male and Female Hypertensive Rats

2020 ◽  
Vol 21 (2) ◽  
pp. 526 ◽  
Author(s):  
Barbara Szeiffova Bacova ◽  
Jana Radosinska ◽  
Gerd Wallukat ◽  
Miroslav Barancik ◽  
Anne Wallukat ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Heart Diseases ◽  
Membrane Integrity ◽  
Omega 3 ◽  
Hypertensive Rats ◽  
Male And Female ◽  
Spontaneously Hypertensive ◽  
Cell Membrane Integrity ◽  
Activity Preservation ◽  
Underlying Mechanisms

The arrhythmogenic potential of β1-adrenoceptor autoantibodies (β1-AA), as well as antiarrhythmic properties of omega-3 in heart diseases, have been reported while underlying mechanisms are poorly understood. We aimed to test our hypothesis that omega-3 (eicosapentaenoic acid-EPA, docosahexaenoic acid-DHA) may inhibit matrix metalloproteinase (MMP-2) activity to prevent cleavage of β1-AR and formation of β1-AA resulting in attenuation of pro-arrhythmic connexin-43 (Cx43) and protein kinase C (PKC) signaling in the diseased heart. We have demonstrated that the appearance and increase of β1-AA in blood serum of male and female 12-month-old spontaneously hypertensive rats (SHR) was associated with an increase of inducible ventricular fibrillation (VF) comparing to normotensive controls. In contrast, supplementation of hypertensive rats with omega-3 for two months suppressed β1-AA levels and reduced incidence of VF. Suppression of β1-AA was accompanied by a decrease of elevated myocardial MMP-2 activity, preservation of cardiac cell membrane integrity and Cx43 topology. Moreover, omega-3 abrogated decline in expression of total Cx43 as well as its phosphorylated forms at serine 368 along with PKC-ε, while decreased pro-fibrotic PKC-δ levels in hypertensive rat heart regardless the sex. The implication of MMP-2 in the action of omega-3 was also demonstrated in cultured cardiomyocytes in which desensitization of β1-AR due to permanent activation of β1-AR with isoproterenol was prevented by MMP-2 inhibitor or EPA. Collectively, these data support the notion that omega-3 via suppression of β1-AA mechanistically controlled by MMP-2 may attenuate abnormal of Cx43 and PKC-ε signaling; thus, abolish arrhythmia substrate and protect rats with an advanced stage of hypertension from malignant arrhythmias.

scholarly journals Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects

2020 ◽  
Author(s):  
Merel Jacobs ◽  
Hannelore P Van Eeckhoutte ◽  
Sara RA Wijnant ◽  
Wim Janssens ◽  
Guy F Joos ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cigarette Smoke ◽  
Lung Tissue ◽  
Bronchial Epithelium ◽  
Chronic Obstructive ◽  
Protein Levels ◽  
Populations At Risk ◽  
Increased Risk ◽  
Entry Receptor ◽  
Severe Copd

ABSTRACTRationaleSmokers and patients with chronic obstructive pulmonary disease (COPD) are at increased risk for severe Coronavirus Disease 2019 (COVID-19).ObjectivesWe investigated the expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor ACE2 and the protease TMPRSS2 in lung tissue from never smokers and smokers with and without COPD.MethodsIn a cross-sectional, observational study we measured mRNA expression of ACE2 and TMPRSS2 by RT-PCR in lung tissue samples from 120 well phenotyped subjects. Next, protein levels of ACE2 were visualized by immunohistochemistry on paraffin sections from 87 subjects and quantified in alveolar and bronchial epithelium. Finally, primary human bronchial epithelial cells (HBECs) were cultured at air liquid interface and exposed to air or cigarette smoke.ResultsACE2 mRNA expression was significantly higher in lung tissue from current smokers and subjects with moderate to very severe COPD and correlated with physiological parameters of airway obstruction and emphysema. Pulmonary expression levels of TMPRSS2 were significantly higher in patients with (very) severe COPD and correlated significantly with ACE2 expression. Importantly, protein levels of ACE2 were elevated in both alveolar and bronchial epithelium of current smokers and subjects with moderate to very severe COPD. Finally, TMPRSS2 mRNA expression increased in in vitro cultured HBECs upon acute exposure to cigarette smoke.ConclusionsWe demonstrate increased expression of ACE2 in lungs of smokers and COPD subjects, which might facilitate host cell entry of SARS-CoV-2. These findings help identifying populations at risk for severe COVID-19.

scholarly journals Cardiac Cx43 and ECM Responses to Altered Thyroid Status Are Blunted in Spontaneously Hypertensive versus Normotensive Rats

2019 ◽  
Vol 20 (15) ◽  
pp. 3758 ◽  
Author(s):  
Matus Sykora ◽  
Barbara Szeiffova Bacova ◽  
Tamara Egan Benova ◽  
Miroslav Barancik ◽  
Jitka Zurmanova ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Connexin 43 ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Omega 3 ◽  
Thyroid Status ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto ◽  
Altered Thyroid

Heart function and its susceptibility to arrhythmias are modulated by thyroid hormones (THs) but the responsiveness of hypertensive individuals to thyroid dysfunction is elusive. We aimed to explore the effect of altered thyroid status on crucial factors affecting synchronized heart function, i.e., connexin-43 (Cx43) and extracellular matrix proteins (ECM), in spontaneously hypertensive rats (SHRs) compared to normotensive Wistar Kyoto rats (WKRs). Basal levels of circulating THs were similar in both strains. Hyperthyroid state (HT) was induced by injection of T3 (0.15 mg/kg b.w. for eight weeks) and hypothyroid state (HY) by the administration of methimazol (0.05% for eight weeks). The possible benefit of omega-3 polyunsaturated fatty acids (Omacor, 200 mg/kg for eight weeks) intake was examined as well. Reduced levels of Cx43 in SHRs were unaffected by alterations in THs, unlike WKRs, in which levels of Cx43 and its phosphorylated form at serine368 were decreased in the HT state and increased in the HY state. This specific Cx43 phosphorylation, attributed to enhanced protein kinase C-epsilon signaling, was also increased in HY SHRs. Altered thyroid status did not show significant differences in markers of ECM or collagen deposition in SHRs. WKRs exhibited a decrease in levels of profibrotic transforming growth factor β1 and SMAD2/3 in HT and an increase in HY, along with enhanced interstitial collagen. Short-term intake of omega-3 polyunsaturated fatty acids did not affect any targeted proteins significantly. Key findings suggest that myocardial Cx43 and ECM responses to altered thyroid status are blunted in SHRs compared to WKRs. However, enhanced phosphorylation of Cx43 at serine368 in hypothyroid SHRs might be associated with preservation of intercellular coupling and alleviation of the propensity of the heart to malignant arrhythmias.

Could Antioxidant Supplementation Delay Progression of Cardiovascular Disease in End-Stage Renal Disease Patients?

2020 ◽  
Vol 19 (1) ◽  
pp. 41-54 ◽  
Author(s):  
Stefanos Roumeliotis ◽  
Athanasios Roumeliotis ◽  
Xenia Gorny ◽  
Peter R. Mertens
Keyword(s):  
Oxidative Stress ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Close Association ◽  
Omega 3 ◽  
Endstage Renal Disease ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

In end-stage renal disease patients, the leading causes of mortality are of cardiovascular (CV) origin. The underlying mechanisms are complex, given that sudden heart failure is more common than acute myocardial infarction. A contributing role of oxidative stress is postulated, which is increased even at early stages of chronic kidney disease, is gradually augmented in parallel to progression to endstage renal disease and is further accelerated by renal replacement therapy. Oxidative stress ensues when there is an imbalance between reactive pro-oxidants and physiologically occurring electron donating antioxidant defence systems. During the last decade, a close association of oxidative stress with accelerated atherosclerosis and increased risk for CV and all-cause mortality has been established. Lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from studies that test antioxidants for CV protection, such as vitamins E and C, statins, omega-3 fatty acids and N-acetylcysteine.

scholarly journals Nutrition as a Key Modifiable Factor for Periodontitis and Main Chronic Diseases

2021 ◽  
Vol 10 (2) ◽  
pp. 197
Author(s):  
Prescilla Martinon ◽  
Laurie Fraticelli ◽  
Agnes Giboreau ◽  
Claude Dussart ◽  
Denis Bourgeois ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Chronic Diseases ◽  
Periodontal Diseases ◽  
Saturated Fat ◽  
Warning Signal ◽  
Dietary Quality ◽  
Omega 3 ◽  
Periodontal Health ◽  
High Fiber ◽  
Increased Risk

Nutrition is recognized as an essential component in the prevention of a number of chronic diseases, including periodontal disease. Based on these considerations, a better understanding is required regarding how the diet, and more particularly the intake of macronutrients and micronutrients, could impact the potential relationship between nutrition and periodontal diseases, periodontal diseases and chronic diseases, nutrition and chronic diseases. To overcome this complexity, an up-to-date literature review on the nutriments related to periodontal and chronic diseases was performed. High-sugar, high-saturated fat, low-polyols, low-fiber and low-polyunsaturated-fat intake causes an increased risk of periodontal diseases. This pattern of nutrients is classically found in the Western diet, which is considered as an ‘unhealthy’ diet that causes cardiovascular diseases, diabetes and cancers. Conversely, low-sugar, high-fiber and high-omega-6-to-omega-3 fatty acid ratio intake reduces the risk of periodontal diseases. The Mediterranean, DASH, vegetarian and Okinawa diets that correspond to these nutritional intakes are considered as ‘healthy’ diets, reducing this risk of cardiovascular diseases, diabetes and cancers. The role of micronutrients, such as vitamin D, E, K and magnesium, remains unclear, while others, such as vitamin A, B, C, calcium, zinc and polyphenols have been shown to prevent PDs. Some evidence suggests that probiotics and prebiotics could promote periodontal health. Periodontal and chronic diseases share, with a time delay, nutrition as a risk factor. Thus, any change in periodontal health should be considered as a warning signal to control the dietary quality of patients and thus reduce the risk of developing chronic diseases later on.

High-Throughput Screening to Identify Small Molecules That Selectively Inhibit APOL1 Protein Level in Podocytes

2021 ◽  
pp. 247255522110262
Author(s):  
Jonathan Choy ◽  
Yanqing Kan ◽  
Steve Cifelli ◽  
Josephine Johnson ◽  
Michelle Chen ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Screening Strategy ◽  
Time Resolved ◽  
Protein Levels ◽  
Increased Risk ◽  
Compound Screening ◽  
High Throughput Screens ◽  
Screening Library

High-throughput phenotypic screening is a key driver for the identification of novel chemical matter in drug discovery for challenging targets, especially for those with an unclear mechanism of pathology. For toxic or gain-of-function proteins, small-molecule suppressors are a targeting/therapeutic strategy that has been successfully applied. As with other high-throughput screens, the screening strategy and proper assays are critical for successfully identifying selective suppressors of the target of interest. We executed a small-molecule suppressor screen to identify compounds that specifically reduce apolipoprotein L1 (APOL1) protein levels, a genetically validated target associated with increased risk of chronic kidney disease. To enable this study, we developed homogeneous time-resolved fluorescence (HTRF) assays to measure intracellular APOL1 and apolipoprotein L2 (APOL2) protein levels and miniaturized them to 1536-well format. The APOL1 HTRF assay served as the primary assay, and the APOL2 and a commercially available p53 HTRF assay were applied as counterscreens. Cell viability was also measured with CellTiter-Glo to assess the cytotoxicity of compounds. From a 310,000-compound screening library, we identified 1490 confirmed primary hits with 12 different profiles. One hundred fifty-three hits selectively reduced APOL1 in 786-O, a renal cell adenocarcinoma cell line. Thirty-one of these selective suppressors also reduced APOL1 levels in conditionally immortalized human podocytes. The activity and specificity of seven resynthesized compounds were validated in both 786-O and podocytes.

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