Myeloid Mineralocorticoid Receptor Transcriptionally Regulates P-Selectin Glycoprotein Ligand-1 and Promotes Monocyte Trafficking and Atherosclerosis

Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex. Approach and Results: We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity. Conclusions: These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation.

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The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

Current Pharmaceutical Design ◽

10.2174/1381612825666190830175424 ◽

2019 ◽

Vol 25 (29) ◽

pp. 3098-3111 ◽

Cited By ~ 6

Author(s):

Luca Liberale ◽

Giovanni G. Camici

Keyword(s):

Atherosclerotic Plaque ◽

Molecular Mechanisms ◽

Driving Forces ◽

Plaque Burden ◽

Vascular Aging ◽

Age Related ◽

Plaque Development ◽

Increased Risk ◽

The Impact ◽

Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

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PKCδ Mediates Mineralocorticoid Receptor Activation by Angiotensin II to Modulate Smooth Muscle Cell Function

Endocrinology ◽

10.1210/en.2019-00258 ◽

2019 ◽

Vol 160 (9) ◽

pp. 2101-2114 ◽

Cited By ~ 2

Author(s):

Qing Lu ◽

Ana P Davel ◽

Adam P McGraw ◽

Sitara P Rao ◽

Brenna G Newfell ◽

...

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Mineralocorticoid Receptor ◽

Target Gene ◽

Cell Function ◽

Receptor Activation ◽

Serine Phosphorylation ◽

Dependent Manner ◽

Responsive Element ◽

The Impact

Abstract Angiotensin II (AngII) and the mineralocorticoid receptor (MR) ligand aldosterone both contribute to cardiovascular disorders, including hypertension and adverse vascular remodeling. We previously demonstrated that AngII activates MR-mediated gene transcription in human vascular smooth muscle cells (SMCs), yet the mechanism and the impact on SMC function are unknown. Using an MR-responsive element-driven transcriptional reporter assay, we confirm that AngII induces MR transcriptional activity in vascular SMCs and endothelial cells, but not in Cos1 or human embryonic kidney-293 cells. AngII activation of MR was blocked by the MR antagonist spironolactone or eplerenone and the protein kinase C-δ (PKCδ) inhibitor rottlerin, implicating both in the mechanism. Similarly, small interfering RNA knockdown of PKCδ in SMCs prevented AngII-mediated MR activation, whereas knocking down of MR blocked both aldosterone- and AngII-induced MR function. Coimmunoprecipitation studies reveal that endogenous MR and PKCδ form a complex in SMCs that is enhanced by AngII treatment in association with increased serine phosphorylation of the MR N terminus. AngII increased mRNA expression of the SMC-MR target gene, FKBP51, via an MR-responsive element in intron 5 of the FKBP51 gene. The impact of AngII on FKBP51 reporter activity and gene expression in SMCs was inhibited by spironolactone and rottlerin. Finally, the AngII-induced increase in SMC number was also blocked by the MR antagonist spironolactone and the PKCδ inhibitor rottlerin. These data demonstrate that AngII activates MR transcriptional regulatory activity, target gene regulation, and SMC proliferation in a PKCδ-dependent manner. This new mechanism may contribute to synergy between MR and AngII in driving SMC dysfunction and to the cardiovascular benefits of MR and AngII receptor blockade in humans.

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Emerging Role of Microbiome in the Prevention of Urinary Tract Infections in Children

International Journal of Molecular Sciences ◽

10.3390/ijms23020870 ◽

2022 ◽

Vol 23 (2) ◽

pp. 870

Author(s):

Anna Kawalec ◽

Danuta Zwolińska

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Urinary Tract Infections ◽

Pediatric Population ◽

Urologic Diseases ◽

Increased Risk ◽

Tract Infections ◽

The Impact

The microbiome of the urinary tract plays a significant role in maintaining health through the impact on bladder homeostasis. Urobiome is of great importance in maintaining the urothelial integrity and preventing urinary tract infection (UTI), as well as promoting local immune function. Dysbiosis in this area has been linked to an increased risk of UTIs, nephrolithiasis, and dysfunction of the lower urinary tract. However, the number of studies in the pediatric population is limited, thus the characteristic of the urobiome in children, its role in a child’s health, and pediatric urologic diseases are not completely understood. This review aims to characterize the healthy urobiome in children, the role of dysbiosis in urinary tract infection, and to summarize the strategies to modification and reshape disease-prone microbiomes in pediatric patients with recurrent urinary tract infections.

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Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease

Biomolecules ◽

10.3390/biom8030096 ◽

2018 ◽

Vol 8 (3) ◽

pp. 96 ◽

Cited By ~ 5

Author(s):

Stefania Gorini ◽

Vincenzo Marzolla ◽

Caterina Mammi ◽

Andrea Armani ◽

Massimiliano Caprio

Keyword(s):

Mineralocorticoid Receptor ◽

Cardiac Fibrosis ◽

Organ Damage ◽

Receptor Activation ◽

High Plasma ◽

Vascular Effects ◽

Cardiometabolic Diseases ◽

End Organ Damage ◽

Potential Biomarkers

The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome.

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The Potential Role of Human Papillomavirus Infection in Bell's Palsy: A Hypothesis-Generating Study Based on a Nationwide Cohort

Frontiers in Medicine ◽

10.3389/fmed.2021.616873 ◽

2021 ◽

Vol 8 ◽

Author(s):

Kuan-Ying Li ◽

Mei-Chia Chou ◽

Renin Chang ◽

Hei-Tung Yip ◽

Yao-Min Hung ◽

...

Keyword(s):

Human Papillomavirus ◽

Index Date ◽

Hpv Infection ◽

Bell’S Palsy ◽

Sensitivity Analyses ◽

Chronic Obstructive ◽

Bell's Palsy ◽

Increased Risk ◽

The Impact

Objective: Our purpose was to investigate whether people with a previous human papillomavirus (HPV) infection were associated with an increased risk of Bell's palsy (BP).Methods: By using Taiwan population-based data, patients aged > 18 years with HPV infection (n = 22,260) from 2000 to 2012 were enrolled and compared with control subjects who had never been diagnosed with an HPV infection at a 1:4 ratio matched by sex, age, index date, and co-morbidities (n = 89,040). The index date was the first date of HPV diagnosis. All the patients were tracked until the occurrence of BP. Cox proportional hazards regression was applied to estimate the hazard ratios (HRs) for the development of BP in both groups.Results: The HPV group had 1.25 [95% confidence interval (CI) = 1.03–1.51] times higher risk of BP compared with the non-HPV group after adjusting for sex, age, and co-morbidities. The association of HPV and BP was significant in the sensitivity analyses. In the subgroup analysis, the impact of HPV infection on the risk of BP was more pronounced in the elderly > 50 years [adjusted hazard ratio (aHR) =1.86; 95% CI = 1.37–2.52], hypertension (aHR = 1.65; 95% CI = 1.17–2.31), and chronic obstructive pulmonary disease (aHR = 2.14, 95% CI 1.333.43) subgroups.Conclusions: Patients with HPV infection have a higher risk of subsequent BP compared with non-HPV patients. More rigorous studies are needed to confirm if and how specific HPV genotypes are associated with BP and the possible role of vaccines in disease prevention.

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The Association of Plant-Based Diet With Cardiovascular Disease and Mortality: A Meta-Analysis and Systematic Review of Prospect Cohort Studies

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.756810 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jingxuan Quek ◽

Grace Lim ◽

Wen Hui Lim ◽

Cheng Han Ng ◽

Wei Zheng So ◽

...

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Mortality ◽

Lower Risk ◽

Meta Analysis ◽

Clinical Endpoints ◽

Hazard Ratios ◽

Increased Risk ◽

The Impact ◽

Dietary Indices

Background: The association between plant-based diets and cardiovascular disease (CVD) remains poorly characterized. Given that diet represents an important and a modifiable risk factor, this study aimed to assess (1) the relationships between the impact of adherence to plant-based diets on cardiovascular mortality, incident CVD, and stroke; (2) if associations differed by adherence to healthful and less healthful plant-based diets.Methods and Findings: MEDLINE and EMBASE databases were searched up to May 2021. Studies assessing CVD outcomes with relation to plant-based dietary patterns or according to plant-based dietary indices (PDI) were included. A meta-analysis of hazard ratios (HR) was conducted using DerSimonian and Laird random effects model. Thirteen studies involving 410,085 participants were included. Greater adherence to an overall plant-based dietary pattern was significantly associated with a lower risk of cardiovascular mortality (pooled HR: 0.92, 95% CI: 0.86–0.99 p = 0.0193, I2 = 88.5%, N = 124,501) and a lower risk of CVD incidence (pooled HR: 0.90, 95% CI: 0.82–0.98, p = 0.0173, I2 = 87.2%, N = 323,854). Among the studies that used PDI, unhealthful plant-based diets were associated with increased risk of cardiovascular mortality (pooled HR: 1.05, 95% CI: 1.01–1.09, p = 0.0123, I2 = 0.00%, N = 18,966), but not CVD incidence. Conversely, healthful plant-based diets were associated with decreased CVD incidence (pooled HR: 0.87, 95% CI: 0.80–0.95, p = 0.0011, I2 = 57.5%, N = 71,301), but not mortality. Vegetarians also had significantly lower CVD incidence (HR: 0.81, 95% CI: 0.72–0.91, p = 0.0004, I2 = 22.2%, N = 16,254), but similar CVD mortality or stroke risk when compared to the meat-eaters.Conclusion: To date, this comprehensive study examines the effects of a plant-based diet on major clinical endpoints using more holistic PDIs. These findings highlight the favorable role of healthful plant-based foods in reducing cardiovascular mortality and CVD.

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A Pilot Study of the Clinical Frailty Scale to Predict Frailty Transition and Readmission in Older Patients in Vietnam

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17051582 ◽

2020 ◽

Vol 17 (5) ◽

pp. 1582

Author(s):

Tan Van Nguyen ◽

Thuy Thanh Ly ◽

Tu Ngoc Nguyen

Keyword(s):

Pilot Study ◽

Older Patients ◽

Rural And Remote ◽

Clinical Frailty Scale ◽

Frailty Status ◽

Phone Calls ◽

Increased Risk ◽

Rural And Remote Areas ◽

The Impact

Background. The Clinical Frailty Scale (CFS) is gaining increasing acceptance due to its simplicity and applicability. Aims. This pilot study aims to examine the role of CFS in identifying the prevalence of frailty, frailty transition, and the impact of frailty on readmission after discharge in older hospitalized patients. Methods. Patients aged ≥60 admitted to the geriatric ward of a hospital in Vietnam were recruited from 9/2018–3/2019 and followed for three months. Frailty was assessed before discharge and after three months, using the CFS (robust: score 1–2, pre-frail: 3–4, and frail: ≥5). Multivariate logistic regression was applied to investigate the associated factors of frailty transition and the impact of frailty on readmission. Results. There were 364 participants, mean age 74.9, 58.2% female. At discharge, 4 were robust, 160 pre-frail, 200 frail. Among the 160 pre-frail participants at discharge, 124 (77.5%) remained pre-frail, and 36 (22.5%) became frail after 3 months. Age (adjusted OR1.09, 95% CI 1.03–1.16), number of chronic diseases (adjusted OR 1.37, 95% CI 1.03–1.82), and polypharmacy at discharge (adjusted OR 3.68, 95% CI 1.15–11.76) were significant predictors for frailty after 3 months. A frailty status at discharge was significantly associated with increased risk of readmission (adjusted OR2.87, 95% CI 1.71–4.82). Conclusions. Frailty was present in half of the participants and associated with increased risk of readmission. This study suggests further studies to explore the use of the CFS via phone calls for monitoring patients’ frailty status after discharge, which may be helpful for older patients living in rural and remote areas.

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Placental ischemia-induced increases in brain water content and cerebrovascular permeability: role of TNF-α

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00372.2015 ◽

2015 ◽

Vol 309 (11) ◽

pp. R1425-R1431 ◽

Cited By ~ 16

Author(s):

Junie P. Warrington ◽

Heather A. Drummond ◽

Joey P. Granger ◽

Michael J. Ryan

Keyword(s):

Water Content ◽

Brain Water Content ◽

Pregnant Rats ◽

Increased Risk ◽

Tnf Α ◽

Bbb Permeability ◽

The Impact ◽

Placental Ischemia ◽

Brain Water

Cerebrovascular complications and increased risk of encephalopathies are characteristic of preeclampsia and contribute to 40% of preeclampsia/eclampsia-related deaths. Circulating tumor necrosis factor-α (TNF-α) is elevated in preeclamptic women, and infusion of TNF-α into pregnant rats mimics characteristics of preeclampsia. While this suggests that TNF-α has a mechanistic role to promote preeclampsia, the impact of TNF-α on the cerebral vasculature during pregnancy remains unclear. We tested the hypothesis that TNF-α contributes to cerebrovascular abnormalities during placental ischemia by first infusing TNF-α in pregnant rats (200 ng/day ip, from gestational day 14 to 19) at levels to mimic those reported in preeclamptic women. TNF-α increased mean arterial pressure (MAP, P < 0.05) and brain water content in the anterior cerebrum ( P < 0.05); however, TNF-α infusion had no effect on blood-brain barrier (BBB) permeability in the anterior cerebrum or posterior cerebrum. We then assessed the role of endogenous TNF-α in mediating these abnormalities in a model of placental ischemia induced by reducing uterine perfusion pressure followed by treatment with the soluble TNF-α receptor (etanercept, 0.8 mg/kg sc) on gestational day 18. Etanercept reduced placental ischemia-mediated increases in MAP, anterior brain water content ( P < 0.05), and BBB permeability (202 ± 44% in placental ischemic rats to 101 ± 28% of normal pregnant rats). Our results indicate that TNF-α mechanistically contributes to cerebral edema by increasing BBB permeability and is an underlying factor in the development of cerebrovascular abnormalities associated with preeclampsia complicated by placental ischemia.

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Effect of chronic treatment of combined statins and aspirin on the risk of prostate cancer detection.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.185 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 185-185

Author(s):

Cristina Suarez ◽

Rafael Morales ◽

Jose Placer ◽

Isaac Nunez ◽

Jacques Planas ◽

...

Keyword(s):

Prostate Cancer ◽

Multivariate Analysis ◽

Chronic Treatment ◽

Univariate Analysis ◽

Combined Treatment ◽

Adult Men ◽

Cancer Aggressiveness ◽

Increased Risk ◽

The Impact

185 Background: The role of chronic treatment (ChT) with statins and aspirin on prostate cancer (PC) carcinogenesis is controversial. Both drugs are frequently used in adult men who are at risk of PC, and many of them receive both drugs simultaneously. The impact of the combined treatment (CT) with statins and aspirin on PC risk has never been reported. We proposed to explore the influence of ChT with statins and aspirin in the PC risk detection and their aggressiveness. Methods: 2408 men were consecutively biopsied for cause: PSA > 4 ng/mL (64.4%), abnormal DRE (9%) or both (26.6%). ChT with statins and aspirin (>1 year) was controlled. Median age was 68 years (46–86) and median PSA 7.0 ng/mL (0.7-1279). At least 10 cores, plus 1 to 8 additional cores, were obtained. The PC detection rate was 35.2% and the Gleason score was < 7 in 20.8%, 7 in 50.9% and > 7 (HGPC) in 28.3%. Multivariate and univariate analysis were done and OR calculated to analyze the strength of the relationships. Results: 440 men (18.3%) were receiving statins alone (SA), 160 (6.6%) aspirin alone (AA), and 304 (12.6%) both drugs simultaneously. Multivariate analysis showed that CT was the only independent predictor of a reduced risk of PC detection, p=0.025, (OR 0.589, 95%CI 0.370-0-936). PC was detected in 552 of 1502 men (36.7%) not receiving statins or aspirin, 34.5% (152/440) receiving SA, 40% (64/160) receiving AA, and in 26.3% (80/304) receiving statins and aspirin simultaneously. Related to cancer aggressiveness, multivariate analysis showed that combined treatment predicted significantly an increased risk of HGPC, p=0.013, (OR 2.672, 95%CI 1.226-5.825). HGPC was detected in 136 of 552 (24.6%) PCs detected in men not receiving statins or aspirin, in 40 of 152 (26.3%) PCs detected in men receiving SA, in 24 of 64 (37.7%) PCs detected in men receiving AA, and in 40 of 80 (50%) PCs detected in men receiving statins and aspirin simultaneously. Conclusions: This study suggests that ChT with the combination of statins and aspirin reduce significantly the risk of PC detection in men subjected to prostate biopsy for cause. However, this reduction of PC detection is accompanied by a significant increase of PC aggressiveness.

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