Abstract MP13: TRPM7 Downregulation Contributes To Cardiovascular Injury And Hypertension Induced By Aldosterone And Salt

TRPM7 has cation channel and kinase properties, is permeable to Mg 2+ , Ca 2+ , and Zn 2+ and is protective in the cardiovascular system. Hyperaldosteronism, which induces hypertension and cardiovascular fibrosis, is associated with Mg 2+ wasting. Here we questioned whether TRPM7 plays a role in aldosterone- induced hypertension and fibrosis and whether it influences cation regulation. Wild-type (WT) and TRPM7-deficient (M7+/Δ) mice were treated with aldosterone (600μg/Kg/day) and/or 1% NaCl (drinking water) (aldo, salt or aldo-salt) for 4 weeks. Blood pressure (BP) was evaluated by tail-cuff. Vessel structure was assessed by pressure myography. Molecular mechanisms were investigated in cardiac fibroblasts (CF) from WT and M7+/Δ mice. Protein expression was assessed by western-blot and histology. M7+/Δ mice exhibited reduced TRPM7 expression (30%) and phosphorylation (62%), levels that were recapitulated in WT aldo-salt mice. M7+/Δ exhibited increased BP by aldo, salt and aldo-salt (135-140mmHg) vs M7+/Δ-veh (117mmHg) (p<0.05), whereas in WT, BP was increased only by aldo-salt (134mmHg). Mesenteric resistance arteries from WT aldo-salt exhibited increased wall/lumen ratio (80%) and reduced internal diameter (15%) whereas vessels from M7+/Δ exhibited thinner walls by reducing cross-sectional area (35%) and increased internal diameter (23%) after aldo-salt. Aldo-salt induced greater collagen deposition in hearts (68%), kidneys (126%) and aortas (45%) from M7+/Δ vs WT. Hearts from M7+/Δ veh exhibited increased TGFβ, IL-11 and IL-6 (1.9-fold), p-Smad3 and p-Stat1 (1.5-fold) whereas in WT these effects were only found after aldo-salt. Cardiac expression of protein phosphatase magnesium-dependent 1A (PPM1A), a Mg 2+ -dependent phosphatase, was reduced (3-fold) only in M7+/Δ mice. M7+/Δ CF showed reduced proliferation (30%) and PPM1A (4-fold) and increased expression of TGFβ, IL-11 and IL-6 (2-3-fold), activation of Stat1 (2-fold), Smad3 (9-fold) and ERK1/2 (8-fold) compared with WT. Mg 2+ supplementation normalized cell proliferation and reduced protein phosphorylation in M7+/Δ CF (p<0.05). Our findings indicate a protective role of TRPM7 in aldosterone-salt induced cardiovascular injury through Mg 2+ -dependent mechanisms.

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MicroRNA-21 ablation exacerbates aldosterone-mediated cardiac injury, remodeling, and dysfunction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00155.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. E1154-E1167 ◽

Cited By ~ 6

Author(s):

Maryam Syed ◽

Jana P. Ball ◽

Keisa W. Mathis ◽

Michael E. Hall ◽

Michael J. Ryan ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Primary Aldosteronism ◽

Molecular Mechanisms ◽

Cardiac Injury ◽

Renin Angiotensin System ◽

Protective Role ◽

Cross Sectional ◽

Genetic Ablation ◽

Small Noncoding Rnas

Primary aldosteronism is characterized by excess aldosterone secretion by the adrenal gland independent of the renin-angiotensin system and accounts for ~10% of hypertensive patients. Excess aldosterone causes cardiac hypertrophy, fibrosis, inflammation, and hypertension. The molecular mechanisms that trigger the onset and progression of aldosterone-mediated cardiac injury remain incompletely understood. MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that have been implicated in multiple cardiac pathologies; however, their regulation and role in aldosterone-mediated cardiac injury and dysfunction remains mostly unknown. We previously reported that microRNA-21 (miR-21) is the most upregulated miRNA by excess aldosterone in the left ventricle in a rat experimental model of primary aldosteronism. To elucidate the role of miR-21 in aldosterone-mediated cardiac injury and dysfunction, miR-21 knockout mice and their wild-type littermates were treated with aldosterone infusion and salt in the drinking water for 2 or 8 wk. miR-21 genetic ablation exacerbated aldosterone/salt-mediated cardiac hypertrophy and cardiomyocyte cross-sectional area. Furthermore, miR-21 genetic ablation increased the cardiac expression of fibrosis and inflammation markers and fetal gene program. miR-21 genetic ablation increased aldosterone/salt-mediated cardiac dysfunction but did not affect aldosterone/salt-mediated hypertension. miR-21 target gene Sprouty 2 may be implicated in the cardiac effects of miR-21 genetic ablation. Our study shows that miR-21 genetic ablation exacerbates aldosterone/salt-mediated cardiac hypertrophy, injury, and dysfunction blood pressure independently. These results suggest that miR-21 plays a protective role in the cardiac pathology triggered by excess aldosterone. Furthermore, miR-21 supplementation may be a novel therapeutic approach to abolish or mitigate excess aldosterone-mediated cardiovascular deleterious effects in primary aldosteronism.

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Protective role of peroxiredoxin-4 in heart failure

Clinical Science ◽

10.1042/cs20191072 ◽

2020 ◽

Vol 134 (1) ◽

pp. 71-72

Author(s):

Naseer Ahmed ◽

Masooma Naseem ◽

Javeria Farooq

Keyword(s):

Heart Failure ◽

Cardiac Fibroblasts ◽

Protective Role ◽

Oxidative Stress Markers ◽

Stress Markers ◽

Total Antioxidant ◽

Galectin 3 ◽

Consequent Increase ◽

And Oxidative Stress

Abstract Recently, we have read with great interest the article published by Ibarrola et al. (Clin. Sci. (Lond.) (2018) 132, 1471–1485), which used proteomics and immunodetection methods to show that Galectin-3 (Gal-3) down-regulated the antioxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. Authors concluded that ‘antioxidant activity of Prx-4 had been identified as a protein down-regulated by Gal-3. Moreover, Gal-3 induced a decrease in total antioxidant capacity which resulted in a consequent increase in peroxide levels and oxidative stress markers in cardiac fibroblasts.’ We would like to point out some results stated in the article that need further investigation and more detailed discussion to clarify certain factors involved in the protective role of Prx-4 in heart failure.

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Circular RNA mmu_circ_0005019 inhibits fibrosis of cardiac fibroblasts and reverses electrical remodeling of cardiomyocytes

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02128-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Na Wu ◽

Chengying Li ◽

Bin Xu ◽

Ying Xiang ◽

Xiaoyue Jia ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cardiac Fibroblasts ◽

Circular Rna ◽

Protective Role ◽

Luciferase Reporter ◽

Loss Of Function ◽

Candidate Target ◽

Paired Control ◽

Reporter Assays ◽

And Migration

Abstract Background Circular RNA (circRNA) have been reported to play important roles in cardiovascular diseases including myocardial infarction and heart failure. However, the role of circRNA in atrial fibrillation (AF) has rarely been investigated. We recently found a circRNA hsa_circ_0099734 was significantly differentially expressed in the AF patients atrial tissues compared to paired control. We aim to investigate the functional role and molecular mechanisms of mmu_circ_0005019 which is the homologous circRNA in mice of hsa_circ_0099734 in AF. Methods In order to investigate the effect of mmu_circ_0005019 on the proliferation, migration, differentiation into myofibroblasts and expression of collagen of cardiac fibroblasts, and the effect of mmu_circ_0005019 on the apoptosis and expression of Ito, INA and SK3 of cardiomyocytes, gain- and loss-of-function of cell models were established in mice cardiac fibroblasts and HL-1 atrial myocytes. Dual-luciferase reporter assays and RIP were performed to verify the binding effects between mmu_circ_0005019 and its target microRNA (miRNA). Results In cardiac fibroblasts, mmu_circ_0005019 showed inhibitory effects on cell proliferation and migration. In cardiomyocytes, overexpression of mmu_circ_0005019 promoted Kcnd1, Scn5a and Kcnn3 expression. Knockdown of mmu_circ_0005019 inhibited the expression of Kcnd1, Kcnd3, Scn5a and Kcnn3. Mechanistically, mmu_circ_0005019 exerted biological functions by acting as a miR-499-5p sponge to regulate the expression of its target gene Kcnn3. Conclusions Our findings highlight mmu_circ_0005019 played a protective role in AF development and might serve as an attractive candidate target for AF treatment.

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Exogenous application of methyl jasmonate induces defense response and develops tolerance against mungbean yellow mosaic India virus in Vigna mungo

Functional Plant Biology ◽

10.1071/fp18168 ◽

2019 ◽

Vol 46 (1) ◽

pp. 69 ◽

Cited By ~ 6

Author(s):

Nibedita Chakraborty ◽

Jolly Basak

Keyword(s):

Methyl Jasmonate ◽

Molecular Mechanisms ◽

Stability Index ◽

Protective Role ◽

Membrane Stability ◽

Vigna Mungo ◽

Marker Genes ◽

Exogenous Application ◽

Ros Homeostasis

Vigna mungo (L.)Hepper is an economically important leguminous crop in south-east Asia. However, its production is severely affected by Mungbean yellow mosaic India virus (MYMIV). It is well established that methyl jasmonate (MeJA) is effective in inducing resistance against pathogens in several plants. To assess the role of MeJA in developing MYMIV tolerance in V. mungo, we analysed time-dependent biochemical and molecular responses of MYMIV susceptible V. mungo after exogenous application of different MeJA concentrations, followed by MYMIV infection. Our analysis revealed that exogenous application of different concentrations of MeJA resulted in decreased levels of malondialdehyde with higher membrane stability index values in MYMIV susceptible V. mungo, suggesting the protective role of MeJA through restoring the membrane stability. Moreover, the level of expression of different antioxidative enzymes revealed that exogenous MeJA is also very effective in ROS homeostasis maintenance. Enhanced expressions of the defence marker genes lipoxygenase and phenylalanine ammonia-lyase and the reduced expression of the MYMIV coat-protein encoding gene in all MeJA treated plants post MYMIV infection revealed that exogenous application of MeJA is effective for MYMIV tolerance in V. mungo. Our findings provide new insights into the physiological and molecular mechanisms of MYMIV tolerance in Vigna induced by MeJA.

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Differential Activation of Fetal Hofbauer Cells in Primigravidas Is Associated with Decreased Birth Weight in Symptomatic Placental Malaria

Malaria Research and Treatment ◽

10.1155/2019/1378174 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Stephanie L. Gaw ◽

Bethann S. Hromatka ◽

Sadiki Ngeleza ◽

Sirirak Buarpung ◽

Nida Ozarslan ◽

...

Keyword(s):

Birth Weight ◽

Placental Malaria ◽

Perinatal Outcomes ◽

Protective Role ◽

Cross Sectional ◽

Macrophage Response ◽

Hofbauer Cells ◽

Infant Birth ◽

First Time

Background. Placental malaria is a leading global cause of low birth weight neonates, especially in first-time mothers. To better understand the role of innate immunity in placental malaria, we investigated the relationships between histopathological markers of placental malaria, fetal and maternal macrophage responses, and perinatal outcomes in a cross-sectional case control study of pregnant women presenting with symptomatic malaria at the time of delivery. Results. Primigravidas showed increased hemozoin deposition in placental villi (p=0.02), syncytiotrophoblasts (p=0.01), and fetal Hofbauer cells (p=0.01). The percentage of hemozoin-positive villi negatively correlated with infant birth weight (regression coefficient [b] = -0.03 kg decrease in birth weight per % increase in hemozoin-positive villi, p=0.035). Malaria-infected placentas showed a twofold increase in Hofbauer cells (p<0.001) and maternal macrophages (p<0.001). Placental malaria was associated with a threefold increase in the percentage of M2 maternal macrophages (19.2% vs 6.4%, p=0.01). Primigravidas showed a significant decrease in the Hofbauer cell M2-percentage in placental malaria (92.7% vs. 97.0%, p=0.04), which was predictive of infant birth weight (b=0.08 kg increase in birth weight per % increase in M2 Hofbauer cells, p=0.001). There was no association between maternal macrophage response and infant birth weights. Conclusions. Placentas with malarial infection had increased numbers of fetal Hofbauer cells in the villous stroma and maternal macrophages in the intervillous space. In primigravidas, decreased anti-inflammatory M2-type Hofbauer cells were predictive of lower birth weight. M2-type maternal macrophages were increased in placental malaria, but there was no association with gravidity or birth weight. These results suggested a protective role of M2 Hofbauer cells in fetal growth restriction.

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Possible protective role of metformin therapy on colonic polyps in acromegaly: an exploratory cross-sectional study

Acta Endocrinologica ◽

10.1530/eje-20-0795 ◽

2021 ◽

Vol 184 (3) ◽

pp. 423-429

Author(s):

M Albertelli ◽

E Nazzari ◽

A Dotto ◽

L F Grasso ◽

S Sciallero ◽

...

Keyword(s):

Acetylsalicylic Acid ◽

Disease Duration ◽

Colonic Polyps ◽

Cross Sectional Study ◽

Protective Role ◽

Diabetic Patients ◽

Sectional Study ◽

Cross Sectional ◽

Acid Intake

Context Colonic polyps occur in 30–40% of acromegalic patients, increasing the risk of colon carcinoma. Although debated, there is emerging evidence that metformin may play a protective role in diabetic and non-diabetic patients with colonic polyps and its use in chemoprevention is currently explored. Objective Evaluate the prevalence of colonic polyps in acromegalic patients treated or not with metformin and explore its possible protective role. Design Exploratory cross-sectional study in two tertiary Italian referral centres. Met hods: Out of 153 acromegalic patients, we selected 58 patients (36–82 years; f: 33) who had at least one colonoscopy performed within the first 2 years of diagnosis. Presence of colonic polyps/cancer and related risk factors, current metformin and acetylsalicylic acid intake, disease duration, therapies for acromegaly, hormonal and metabolic parameters were assessed. Results An overall prevalence of 36% polyps was found. Based on the presence of polyps, we identified two groups, comparable for age, BMI, disease duration, glucose, insulin, HOMA-IR, HbA1c, GH and IGF-I levels. Of the patients with polyps (including three adenocarcinomas) only 24% were treated with metformin vs 57% of patients without polyps. Multivariate analysis confirmed a significant negative association between colonic polyps and metformin intake (OR: 0.22, 95% CI: 0.06-0.77, P = 0.01), whereas no significant association was found between polyps and age (P = 0.10), overweight/obesity (P = 0.54), smoking (P = 0.15), acetylsalicylic acid intake (P = 0.99), disease duration (P = 0.96), somatostatin analogues treatment (P = 0.70). Conclusions These findings, though deriving from an exploratory study, could suggest a protective role of metformin on the development of colonic polyps in acromegaly, and need to be confirmed in an extended study population.

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(Letter to the Editor) Response to: protective role of peroxiredoxin-4 in heart failure

Clinical Science ◽

10.1042/cs20191184 ◽

2020 ◽

Vol 134 (1) ◽

pp. 73-74

Author(s):

Natalia López-Andrés

Keyword(s):

Heart Failure ◽

Dilated Cardiomyopathy ◽

Cardiac Fibroblasts ◽

Direct Consequence ◽

Protective Role ◽

Mitochondrial Proteins ◽

Galectin 3 ◽

Human Cardiac Fibroblasts

Abstract We thank Ahmed et al. for their letter regarding our study ‘Galectin-3 down-regulates antioxidant peroxiredoxin-4 in human cardiac fibroblasts’ [1]. As emphasized by Ahmed et al., Prx-4 levels decrease [2] whereas MFN-2, OPA-1 and PGC-1α levels increase [3] in dilated cardiomyopathy (DCM). Moreover, Gal-3 expression is also increased in DCM [4]. In our study, we showed in vitro that Gal-3 decreased Prx-4 without modifying MFN-2 or PGC-1α levels in human cardiac fibroblasts. Although cardiac Prx-4 decrease could be a direct consequence of Gal-3 effects on cardiac fibroblasts, we cannot exclude the possibility that other factors increase MFN-2, OPA-1 and PGC-1α levels in both cardiac fibroblasts or cardiomyocytes in the context of DCM. Further studies are needed to clarify the association between Prx-4 decrease and the increase in other mitochondrial proteins in DCM.

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The Protective Role of Character Strengths in COVID-19 Stress and Well-Being in Individuals With Chronic Conditions and Disabilities: An Exploratory Study

Rehabilitation Counseling Bulletin ◽

10.1177/0034355220967093 ◽

2020 ◽

Vol 64 (2) ◽

pp. 67-74

Author(s):

Emre Umucu ◽

Timothy N. Tansey ◽

Jessica Brooks ◽

Beatrice Lee

Keyword(s):

Chronic Conditions ◽

Character Strengths ◽

Well Being ◽

Cross Sectional Study ◽

Protective Role ◽

Negative Effects ◽

Cross Sectional ◽

Internal Resources ◽

Related Stress

Individuals with chronic conditions and disabilities, in response to stress associated with COVID-19, may experience a decrease in their overall well-being beyond that experienced by otherwise healthy individuals. Therefore, it is imperative to identify internal resources (e.g., character strengths) that can help them better manage COVID-19-related stress and enhance well-being in spite of COVID-19. This study explored the potential protective role of character strengths and virtues in moderating the negative effects of COVID-19 on stress and well-being. A cross-sectional study design was implemented. Participants included 269 individuals with self-reported chronic conditions and disabilities. After controlling for demographic and clinical characteristics, we examined whether character strengths and virtues acted as independent moderators between COVID-19-related stress and well-being. A higher degree of multiple character strengths significantly and independently moderated the relationship between COVID-19-related stress and well-being. Findings suggested the importance of promoting more character strengths overall in people with chronic conditions and disabilities to help them better manage COVID-19-related stress and enhance well-being.

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