Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype

2003 ◽  
Vol 285 (2) ◽  
pp. H813-H821 ◽  
Author(s):  
Ivan C. Gerling ◽  
Yao Sun ◽  
Robert A. Ahokas ◽  
Linus A. Wodi ◽  
Syamal K. Bhattacharya ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Nitrosative Stress ◽  
Mononuclear Cells ◽  
Inflammatory Cells ◽  
Vascular Lesions ◽  
Oxidative And Nitrosative Stress ◽  
Peripheral Blood Mononuclear ◽  
Cardiac Phenotype ◽  
And Gender ◽  
The Right

Chronic inappropriate (relative to dietary Na+intake) elevations in circulating aldosterone (ALDO), termed aldosteronism, are associated with remodeling of intramural arteries of the right and left heart. Lesions appear at week 4 of treatment with ALDO and 1% dietary NaCl in uninephrectomized rats (ALDOST) and include invading monocytes, macrophages and lymphocytes with intracellular evidence of oxidative and nitrosative stress, myofibroblasts, and perivascular fibrosis. In this study, we tested the hypothesis that an immunostimulatory state with activated circulating peripheral blood mononuclear cells (PBMCs) precedes this proinflammatory and profibrogenic cardiac phenotype and is initiated by reduction in the cytosolic free Mg2+concentration ([Mg2+]i). At 1 and 4 wk of ALDOST (preclinical and clinical stages, respectively), we monitored serum Mg2+, PBMC [Mg2+]iand cytosolic free [Ca2+] (via fluorimetry), and expressed genes (via microchip array) as well as markers of oxidative and nitrosative stress in plasma [α1-antiproteinase activity (α1-AP)] and cardiac tissue (immunohistochemical detection of gp91phoxsubunit of NADPH oxidase and 3-nitrotyrosine). Age- and gender-matched unoperated and untreated (UO) rats and uninephrectomized salt-treated (UN) rats served as controls. Serum [Mg2+] was unchanged by ALDOST. In contrast with UO and UN, [Mg2+]iand plasma α1-AP were each reduced ( P < 0.05) at weeks 1 and 4. The decline in PBMC [Mg2+]iwas accompanied by Ca2+loading. Differential (twofold and higher) expression (up- and downregulation) in PBMC transcriptomes was present at week 1 and progressed at week 4. Involved were genes for the α1-isoform of Na+-K+-ATPase, the ATP-dependent Ca2+pump, antioxidant reserves, inducible nitric oxide synthase, and PBMC activation with autoimmune responses. Expression of 3-nitrotyrosine and activation of gp91phoxwere seen in inflammatory cells that invaded intramural arteries. Thus early in aldosteronism (preclinical stage), an immunostimulatory state featuring activated circulating PBMCs with reduced ionized [Mg2+]iand oxidative and nitrosative stress precedes and may even predispose to coronary vascular lesions that first appear at week 4.

scholarly journals The Changes of Expression and Methylation of Genes Involved in Oxidative Stress in Course of Chronic Mild Stress and Antidepressant Therapy with Agomelatine

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 644
Author(s):  
Paulina Wigner ◽  
Ewelina Synowiec ◽  
Paweł Jóźwiak ◽  
Piotr Czarny ◽  
Michał Bijak ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitrosative Stress ◽  
Mononuclear Cells ◽  
Methylation Status ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Oxidative And Nitrosative Stress ◽  
Peripheral Blood Mononuclear ◽  
Taqman Gene Expression Assay ◽  
The Brain

Preclinical studies conducted so far suggest that oxidative stress processes may be associated with the mechanism of depression development. This study shows the effects of chronic administration of agomelatine on expression and the methylation status of Sod1, Sod2, Gpx1, Gpx4, Cat, Nos1, and Nos2 in the brain stricture and blood in the chronic mild stress (CMS) animal model of depression. The animals were exposed to the CMS procedure and treatment with agomelatine (10 mg/kg/day, IP) for five weeks and then were sacrificed. TaqMan Gene Expression Assay, Western blot, and methylation-sensitive high-resolution melting techniques were used to evaluate mRNA and protein expression of the genes, and the methylation status of their promoters. Gpx1, Gpx4, and Sod2 expression in the PBMCs and Sod1 and Sod2 expression in the brain were reduced in the stressed group after agomelatine administration. CMS caused an increase in the methylation of the third Gpx4 promoter in peripheral blood mononuclear cells and Gpx1 promoter in the cerebral cortex. Additionally, stressed rats treated with agomelatine displayed a significantly lower Gpx4 level in the hypothalamus. The results confirm the hypothesis that the CMS procedure and agomelatine administration change the expression level and methylation status of the promoter region of genes involved in oxidative and nitrosative stress.

scholarly journals Anti-inflammatory genes in PBMCs post-spontaneous intracerebral hemorrhage

2021 ◽  
Vol 12 (1) ◽  
pp. 58-66
Author(s):  
Doan Nguyen ◽  
Vi Tran ◽  
Alireza Shirazian ◽  
Cruz Velasco-Gonzalez ◽  
Ifeanyi Iwuchukwu
Keyword(s):  
Intracerebral Hemorrhage ◽  
Negative Correlation ◽  
Mononuclear Cells ◽  
Inflammatory Cells ◽  
Favorable Outcome ◽  
Hospital Length Of Stay ◽  
Spontaneous Intracerebral Hemorrhage ◽  
Hematoma Volume ◽  
Peripheral Blood Mononuclear ◽  
Anti Inflammatory

Abstract Background Neuroinflammation is important in the pathophysiology of spontaneous intracerebral hemorrhage (ICH) and peripheral inflammatory cells play a role in the clinical evolution and outcome. Methodology Blood samples from ICH patients (n = 20) were collected at admission for 5 consecutive days for peripheral blood mononuclear cells (PBMCs). Frozen PBMCs were used for real-time PCR using Taqman probes (NFKB1, SOD1, PPARG, IL10, NFE2L2, and REL) and normalized to GAPDH. Data on hospital length of stay and modified Rankin score (MRS) were collected with 90-day MRS ≤ 3 as favorable outcome. Statistical analysis of clinical characteristics to temporal gene expression from early to delayed timepoints was compared for MRS groups (favorable vs unfavorable) and hematoma volume. Principle findings and results IL10, SOD1, and REL expression were significantly higher at delayed timepoints in PBMCs of ICH patients with favorable outcome. PPARG and REL increased between timepoints in patients with favorable outcome. NFKB1 expression was not sustained, but significantly decreased from higher levels at early onset in patients with unfavorable outcome. IL10 expression showed a negative correlation in patients with high hematoma volume (>30 mL). Conclusions and significance Anti-inflammatory, pro-survival regulators were highly expressed at delayed time points in ICH patients with a favorable outcome, and IL10 expression showed a negative correlation to high hematoma volume.

Cellular Bioenergetic and Metabolic Changes in Patients with Autism Spectrum Disorder

2021 ◽  
Vol 21 ◽  
Author(s):  
Maria Gevezova ◽  
Danail Minchev ◽  
Iliana Pacheva ◽  
Yordan Sbirkov ◽  
Ralitsa Yordanova ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mononuclear Cells ◽  
Cell Metabolism ◽  
Strong Dependence ◽  
Autism Spectrum ◽  
Metabolic Changes ◽  
Spectrum Disorder ◽  
Control Group ◽  
Peripheral Blood Mononuclear ◽  
And Gender

Background: Although Autism Spectrum Disorder (ASD) is considered a heterogeneous neurological disease in childhood, a growing body of evidence associates it with mitochondrial dysfunction explaining the observed comorbidities. Introduction: The aim of this study is to identify variations in cellular bioenergetics and metabolism dependent on mitochondrial function in ASD patients and healthy controls using peripheral blood mononuclear cells (PBMCs). We hypothesized that PBMCs may reveal the cellular pathology and provide evidence of bioenergetic and metabolic changes accompanying the disease. Method: PBMC from children with ASD and a control group of the same age and gender were isolated. All patients underwent an in-depth clinical evaluation. A well-characterized cohort of Bulgarian children was selected. Bioenergetic and metabolic studies of isolated PBMCs were performed with a Seahorse XFp analyzer. Result: Our data show that PBMCs from patients with ASD have increased respiratory reserve capacity (by 27.5%), increased maximal respiration (by 67%) and altered adaptive response to oxidative stress induced by DMNQ. In addition, we demonstrate а strong dependence on fatty acids and impaired ability to reprogram cell metabolism. The listed characteristics are not observed in the control group. These results can contribute to a better understanding of the underlying causes of ASD, which is crucial for selecting a successful treatment. Conclusion: The current study, for the first time, provides a functional analysis of cell bioenergetics and metabolic changes in a group of Bulgarian patients with ASD. It reveals physiological abnormalities that do not allow mitochondria to adapt and meet the increased energetic requirements of the cell. The link between mitochondria and ASD is not yet fully understood, but this may lead to the discovery of new approaches for nutrition and therapy.

scholarly journals Virome Sequencing in Patients With Myocarditis

2020 ◽  
Vol 13 (7) ◽  
Author(s):  
Bettina Heidecker ◽  
Simon H. Williams ◽  
Komal Jain ◽  
Alexandra Oleynik ◽  
Dimitri Patriki ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cardiac Tissue ◽  
Mononuclear Cells ◽  
Endogenous Retrovirus ◽  
Fulminant Myocarditis ◽  
Human Endogenous Retrovirus ◽  
Peripheral Blood Mononuclear ◽  
Tissue Samples ◽  
Cardiac Tissues ◽  
Barr Virus

Background: Polymerase chain reaction analyses of cardiac tissues have detected viral sequences in up to 67% of cases of myocarditis. However, viruses have not been implicated in giant cell myocarditis (GCM). Furthermore, efforts to detect viruses implicated in myocarditis have been unsuccessful in more accessible samples such as peripheral blood. Methods: We used Virome Capture Sequencing for Vertbrate Viruses (VirCapSeq-VERT), a method that simultaneously screens for all known vertebrate viruses, to investigate viruses in 33 patients with myocarditis. We investigated peripheral blood mononuclear cells (n=24), plasma (n=27), endomyocardial biopsies (n=2), and cardiac tissue samples from explanted hearts (n=13). Results: Nine patients (27%) had GCM and 4 patients (13%) had fulminant myocarditis. We found the following viruses in the blood of patients with myocarditis: Epstein Barr virus (n=11, 41%), human pegivirus (n=1, 4%), human endogenous retrovirus K (n=27, 100%), and anellovirus (n=15, 56%). All tissue samples from fulminant myocarditis (n=2) and GCM (n=13) contained human endogenous retrovirus K. Conclusions: No nucleic acids from viruses previously implicated in myocarditis or other human illnesses were detected in relevant amounts in cardiac tissue samples from GCM or in blood samples from other types of myocarditis. These findings do not exclude a role for viral infection in GCM but do suggest that if viruses are implicated, the mechanism is likely to be indirect rather than due to cytotoxic infection of myocardium.

scholarly journals Age and gender effects on DNA strand break repair in peripheral blood mononuclear cells

Aging Cell ◽  
2012 ◽  
Vol 12 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Christian Garm ◽  
Maria Moreno-Villanueva ◽  
Alexander Bürkle ◽  
Inge Petersen ◽  
Vilhelm A. Bohr ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Strand Break ◽  
Gender Effects ◽  
Peripheral Blood Mononuclear ◽  
Age And Gender ◽  
Dna Strand Break ◽  
Blood Mononuclear Cells ◽  
And Gender ◽  
Dna Strand

scholarly journals Unravelling Atrioventricular Block Risk in Inflammatory Diseases: Systemic Inflammation Acutely Delays Atrioventricular Conduction via a Cytokine‐Mediated Inhibition of Connexin43 Expression

2021 ◽  
Author(s):  
Pietro Enea Lazzerini ◽  
Maurizio Acampa ◽  
Michael Cupelli ◽  
Alessandra Gamberucci ◽  
Ujala Srivastava ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Inflammatory Markers ◽  
Cardiac Tissue ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Atrioventricular Conduction ◽  
Peripheral Blood Mononuclear ◽  
In Vivo Animal Model

Background Recent data suggest that systemic inflammation can negatively affect atrioventricular conduction, regardless of acute cardiac injury. Indeed, gap‐junctions containing connexin43 coupling cardiomyocytes and inflammation‐related cells (macrophages) are increasingly recognized as important factors regulating the conduction in the atrioventricular node. The aim of this study was to evaluate the acute impact of systemic inflammatory activation on atrioventricular conduction, and elucidate underlying mechanisms. Methods and Results We analyzed: (1) the PR‐interval in patients with inflammatory diseases of different origins during active phase and recovery, and its association with inflammatory markers; (2) the existing correlation between connexin43 expression in the cardiac tissue and peripheral blood mononuclear cells (PBMC), and the changes occurring in patients with inflammatory diseases over time; (3) the acute effects of interleukin(IL)‐6 on atrioventricular conduction in an in vivo animal model, and on connexin43 expression in vitro. In patients with elevated C‐reactive protein levels, atrioventricular conduction indices are increased, but promptly normalized in association with inflammatory markers reduction, particularly IL‐6. In these subjects, connexin43 expression in PBMC, which is correlative of that measured in the cardiac tissue, inversely associated with IL‐6 changes. Moreover, direct IL‐6 administration increased atrioventricular conduction indices in vivo in a guinea pig model, and IL‐6 incubation in both cardiomyocytes and macrophages in culture, significantly reduced connexin43 proteins expression. Conclusions The data evidence that systemic inflammation can acutely worsen atrioventricular conduction, and that IL‐6‐induced down‐regulation of cardiac connexin43 is a mechanistic pathway putatively involved in the process. Though reversible, these alterations could significantly increase the risk of severe atrioventricular blocks during active inflammatory processes.

Glucocorticoid sensitivity of interleukin-1 agonist and antagonist secretion: the effects of age and gender

2000 ◽  
Vol 278 (4) ◽  
pp. R855-R862 ◽  
Author(s):  
Jane M. Daun ◽  
Richard W. Ball ◽  
Joseph G. Cannon
Keyword(s):  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Dependent Manner ◽  
Basal Secretion ◽  
Peripheral Blood Mononuclear ◽  
Age Related ◽  
Agonist And Antagonist ◽  
And Gender ◽  
Dose Dependent ◽  
Pituitary Adrenal Axis

Interleukin-1 (IL-1) is a primary mediator of inflammation that is regulated, in part, by the hypothalamic-pituitary-adrenal axis. The purpose of this study was to determine if gender- or age-related differences exist in the sensitivity of IL-1-producing cells to hydrocortisone. Peripheral blood mononuclear cells (PBMC) isolated from men and women (21–77 yr old) were incubated with hydrocortisone (0, 50, 100, 500, or 1,000 ng/ml) with or without lipopolysaccharide (LPS). Secretion of IL-1β and IL-1 receptor antagonist was inhibited in a dose-dependent manner ( P = 0.001) without age- or gender-related differences. Hydrocortisone decreased soluble IL-1 receptor type II (sIL-1RII) secretion by unstimulated cells ( P = 0.0001), but it increased secretion by LPS-stimulated cells ( P = 0.0001) in all groups. Unstimulated cell supernatants from men contained greater concentrations of sIL-1RII than the supernatants from women ( P= 0.011). Compared with men, PBMCs from women were less responsive to hydrocortisone inhibition of sIL-1RII secretion, regardless of age ( P = 0.001), and compared with the follicular phase, sIL-1RII secretion was lower in the luteal phase of the menstrual cycle ( P < 0.05). These data indicate that basal secretion and glucocorticoid modulation of sIL-1RII secretion by cultured PBMCs are gender dependent. Moreover, glucocorticoid influences on sIL-1RII secretion depend on the presence or absence of gram-negative bacterial toxins.

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