scholarly journals The Role of the Mineralocorticoid Receptor in Inflammation: Focus on Kidney and Vasculature

2017 ◽  
Vol 46 (4) ◽  
pp. 298-314 ◽  
Author(s):  
Zachary Belden ◽  
Jeffrey A. Deiuliis ◽  
Mirela Dobre ◽  
Sanjay Rajagopalan
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Smooth Muscle ◽  
Mineralocorticoid Receptor ◽  
Tissue Injury ◽  
Muscle Tone ◽  
Target Organ Damage ◽  
Critical Role ◽  
Macrophage Phenotype

Background: The remarkable success of clinical trials in mineralocorticoid receptor (MR) inhibition in heart failure has driven research on the physiological and pathological role(s) of nonepithelial MR expression. MR is widely expressed in the cardiovascular system and is a major determinant of endothelial function, smooth muscle tone, vascular remodeling, fibrosis, and blood pressure. An important new dimension is the appreciation of the role MR plays in immune cells and target organ damage in the heart, kidney and vasculature, and in the development of insulin resistance. Summary: The mechanism for MR activation in tissue injury continues to evolve with the evidence to date suggesting that activation of MR results in a complex repertoire of effects involving both macrophages and T cells. MR is an important transcriptional regulator of macrophage phenotype and function. Another important feature of MR activation is that it can occur even with normal or low aldosterone levels in pathological conditions. Tissue-specific conditional models of MR expression in myeloid cells, endothelial cells, smooth muscle cells and cardiomyocytes have been very informative and have firmly demonstrated a critical role of MR as a key pathophysiologic variable in cardiac hypertrophy, transition to heart failure, adipose inflammation, and atherosclerosis. Finally, the central nervous system activation of MR in permeable regions of the blood-brain barrier may play a role in peripheral inflammation. Key Message: Ongoing clinical trials will help clarify the role of MR blockade in conditions, such as atherosclerosis and chronic kidney disease.

Bridging the Knowledge Gaps in Arrhythmogenic Cardiovascular Conditions: The Critical Role of Registries

2016 ◽  
Vol 10 (2) ◽  
pp. 1 ◽  
Author(s):  
Melody Hermel ◽  
Rebecca Duffy ◽  
Alexander Orfanos ◽  
Isabelle Hack ◽  
Shayna McEnteggart ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Natural History ◽  
Risk Stratification ◽  
Critical Role ◽  
Knowledge Gaps ◽  
Level Of Evidence ◽  
The Future

Cardiac registries have filled many gaps in knowledge related to arrhythmogenic cardiovascular conditions. Despite the less robust level of evidence available in registries when compared with clinical trials, registries have contributed a range of clinically useful information. In this review, the authors discuss the role that registries have played – related to diagnosis, natural history, risk stratification, treatment, and genetics of arrhythmogenic cardiovascular conditions – in closing knowledge gaps, and their role in the future.

THE ROLE OF MYELOPEROXIDASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S4-S4
Author(s):  
Belal Chami ◽  
Gulfam Ahmad ◽  
Angie Schroder ◽  
Patrick San Gabriel ◽  
Paul Witting
Keyword(s):  
Disease Severity ◽  
Hypochlorous Acid ◽  
Tissue Injury ◽  
Activity Index ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Sodium Sulphate ◽  
Host Tissue ◽  
Neutrophil Extracellular Trap

Abstract Neutrophils are short-lived immune cells that represent the major cell type recruited to the inflamed bowel releasing their azurophilic granules containing enzymes myeloperoxidase (MPO). Fecal and serum MPO levels has previously been shown to correlate to disease severity in IBD patients. MPO, in the presence of H2O2 and free Cl- undergoes a halogenation cycle, yielding the two-electron oxidant, hypochlorous acid (HOCl) - a potent bactericidal agent. However, chronic intestinal exposure to MPO/HOCl due to perpetual inflammation may cause secondary host-tissue injury and cell death. Neutrophil Extracellular Trap (NET)osis is a specialised form of neutrophil death where MPO is entrapped in a DNA scaffold and continues to elicit HOCl activity and may further contribute to host-tissue injury. We investigated the presence of NETs in surgically excised ileum samples from CD and healthy patients using advanced confocal microscopic techniques and found MPO, Neutrophil Elastase (NE) and Citrullinated Histone h3 (CitH3) - critical components of NET formation, individually positively correlate to the severity of histopathological intestinal injury. Furthermore, multiplex Opal™ IHC performed using LMS880 Airyscan-moduled microscopy with z-stacking revealed colocalization of NE, MPO, CitH3 and DAPI indicating the extensive presence of NETs in severely affected CD tissue. Using two pharmacological inhibitors of MPO in a dextran sodium sulphate (DSS) model of murine colitis, we demonstrated the pathological role of MPO in experimental colitis. MPO inhibitors, TEMPOL and AZD3241 delivered via daily i.p significantly rescued the course of colitis by abrogating clinical indices including body weight loss, disease activity index, inhibiting serum peroxidation, and preserving colon length, while significantly mitigating histoarchitectural damage associated with DSS-induced colitis. We also showed that MPO inhibition decreased neutrophil migration to the gut, suggesting MPO may play a role in perpetuating the inflammatory cell by further recruiting cells to the inflamed gut. Collectively, we have shown for the first time that MPO is not only an important clinical marker of disease severity but may also play a critical role in perpetuating host-tissue damage and inflammation.

scholarly journals Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1442
Author(s):  
Pau Vancells Lujan ◽  
Esther Viñas Esmel ◽  
Emilio Sacanella Meseguer
Keyword(s):  
Clinical Trials ◽  
Liver Disease ◽  
Critical Role ◽  
Dietary Treatment ◽  
Dietary Interventions ◽  
Lifestyle Modifications ◽  
Alcoholic Fatty Liver ◽  
Effective Form ◽  
Unhealthy Diet

NAFLD is the world’s most common chronic liver disease, and its increasing prevalence parallels the global rise in diabetes and obesity. It is characterised by fat accumulation in the liver evolving to non-alcoholic steatohepatitis (NASH), an inflammatory subtype that can lead to liver fibrosis and cirrhosis. Currently, there is no effective pharmacotherapeutic treatment for NAFLD. Treatment is therefore based on lifestyle modifications including changes to diet and exercise, although it is unclear what the most effective form of intervention is. The aim of this review, then, is to discuss the role of specific nutrients and the effects of different dietary interventions on NAFLD. It is well established that an unhealthy diet rich in calories, sugars, and saturated fats and low in polyunsaturated fatty acids, fibre, and micronutrients plays a critical role in the development and progression of this disease. However, few clinical trials have evaluated the effects of nutrition interventions on NAFLD. We, therefore, summarise what is currently known about the effects of macronutrients, foods, and dietary patterns on NAFLD prevention and treatment. Most current guidelines recommend low-calorie, plant-based diets, such as the Mediterranean diet, as the most effective dietary pattern to treat NAFLD. More clinical trials are required, however, to identify the best evidence-based dietary treatment approach.

Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury

2014 ◽  
Vol 307 (3) ◽  
pp. H337-H345 ◽  
Author(s):  
Lara Gotha ◽  
Sang Yup Lim ◽  
Azriel B. Osherov ◽  
Rafael Wolff ◽  
Beiping Qiang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Critical Role ◽  
Arterial Injury ◽  
Side Chains ◽  
Wild Type ◽  
Injury Response ◽  
Migratory Response

Perlecan is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2Δ3/Δ3 (MΔ3/Δ3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from MΔ3/Δ3 and wild-type mice. Proliferation of MΔ3/Δ3 SMC was 1.5× greater than in wild type ( P < 0.001), increased by addition of growth factors, and showed a 42% greater migratory response than wild-type cells to PDGF-BB ( P < 0.001). In MΔ3/Δ3 SMC adhesion to fibronectin, and collagen types I and IV was significantly greater than wild type. Addition of DRL-12582, an inducer of perlecan expression, decreased proliferation and migratory response to PDGF-BB stimulation in wild-type SMC compared with MΔ3/Δ3. In an in vivo carotid artery wire injury model, the medial thickness, medial area/lumen ratio, and macrophage infiltration were significantly increased in the MΔ3/Δ3 mice, indicating a prominent role of the HS side chain in limiting vascular injury response. Mutant perlecan that lacks HS side chains had a marked reduction in the inhibition of in vitro SMC function and the in vivo arterial response to injury, indicating the critical role of HS side chains in perlecan function in the vessel wall.

scholarly journals The relevance of prescribing triple neurohormonal blockade in real clinical practice: the role of mineralocorticoid receptor antagonists

2021 ◽  
Vol 23 (6) ◽  
pp. 491-497
Author(s):  
Igor V. Zhirov ◽  
◽  
Igor V. Zhirov ◽  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Mineralocorticoid Receptor ◽  
Systolic Dysfunction ◽  
Term Treatment ◽  
Mineralocorticoid Receptor Antagonists ◽  
Long Term Treatment ◽  
Real Clinical Practice

In the article is outlined the main concepts use of the mineralocorticoids receptors antagonists in the treatment of congestive heart failure and systolic dysfunction after acute myocardial infarction. Claimed the pivotal role of eplerenone in the long-term treatment strategy due to decrease of mortality and improving the clinical outcomes.

Central mineralocorticoid receptor blockade decreases plasma TNF-α after coronary artery ligation in rats

2003 ◽  
Vol 284 (2) ◽  
pp. R328-R335 ◽  
Author(s):  
Joseph Francis ◽  
Robert M. Weiss ◽  
Alan Kim Johnson ◽  
Robert B. Felder
Keyword(s):  
Heart Failure ◽  
Central Nervous System ◽  
Nervous System ◽  
Mineralocorticoid Receptor ◽  
Critical Role ◽  
Evaluation Study ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Tnf Α ◽  
The Central Nervous System

The Randomized Aldactone Evaluation Study (RALES) demonstrated a substantial clinical benefit to blocking the effects of aldosterone (Aldo) in patients with heart failure. We recently demonstrated that the enhanced renal conservation of sodium and water in rats with heart failure can be reduced by blocking the central nervous system effects of Aldo with the mineralocorticoid receptor (MR) antagonist spironolactone (SL). Preliminary data from our laboratory suggested that central MR might contribute to another peripheral mechanism in heart failure, the release of proinflammatory cytokines. In the present study, SL (100 ng/h for 21 days) or ethanol vehicle (Veh) was administered via the 3rd cerebral ventricle to one group of rats after coronary ligation (CL) or sham CL (Sham) to induce congestive heart failure (CHF). In Veh-treated CHF rats, tumor necrosis factor-α (TNF-α) levels increased during day 1 and continued to increase throughout the 3-wk observation period. In CHF rats treated with SL, started 24 h after CL, TNF-α levels rose initially but retuned to control levels by day 5 after CL and remained low throughout the study. These findings suggest that activation of MR in the central nervous system plays a critical role in regulating TNF-α release in heart failure rats. Thus some of the beneficial effect of blocking MR in heart failure could be due at least in part to a reduction in TNF-α production.

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