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1.
Hypertension ; 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38497230

RESUMO

BACKGROUND: The mTOR (mechanistic target of rapamycin) is an essential regulator of fundamental biological processes. mTOR forms 2 distinct complexes, mTORC1 (mTOR complex 1) when it binds with RAPTOR (Regulatory-associated Protein of mTOR) and mTORC2 (mTOR complex 2) when it associates with RICTOR (Rapamycin-insesitive companion of mTOR). Due to the previous link between the mTOR pathway, aldosterone, and blood pressure (BP), we anticipated that variants in the mTOR complex might be associated with salt-sensitive BP. METHODS: BP and other parameters were assessed after a one-week liberal Na+ (200 mmol/d) and a one-week restricted Na+ (10 mmol/d) diet in 608 White subjects from the Hypertensive Pathotype cohort, single-nucleotide variants in MTOR, RPTOR, and RICTOR genes were obtained for candidate genes analyses. RESULTS: The analysis revealed a significant association between a single nucleotide variants within the RPTOR gene and BP. Individuals carrying the RPTOR rs9901846 homozygous risk allele (AA) and heterozygous risk allele (GA) exhibited a 5 mm Hg increase in systolic BP on a liberal diet compared with nonrisk allele individuals (GG), but only in women. This single nucleotide variants effect was more pronounced on the restricted diet and present in both sexes, with AA carriers having a 9 mm Hg increase and GA carriers having a 5 mm Hg increase in systolic BP compared with GG. Interestingly, there were no significant associations between MTOR or RICTOR gene variants and BP. CONCLUSIONS: The RPTOR gene variation is associated with elevated BP in White participants, regardless of salt intake, specifically in females.

2.
Hypertension ; 81(2): 330-339, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38018471

RESUMO

BACKGROUND: Salt sensitivity of blood pressure (SSBP) is a substantial risk factor for cardiovascular morbidity and mortality. Striatin (STRN) is critical for estrogen and aldosterone nongenomic signaling. However, the role of biological sex on the SSBP phenotype associated with STRN gene variants remains unexplored. METHOD: Data from 1306 subjects participating in the Hypertensive Pathotype (HyperPATH) Consortium were used to identify STRN gene single-nucleotide variants associated with SSBP. Haploblock analysis revealed a novel diplotype in the upstream regulatory region of STRN (rs888083 and rs6744560), with 31% of subjects being homozygous for the risk diplotype. RESULTS: Individuals homozygous for the risk diplotype had significantly greater SSBP than nonrisk diplotypes (P<0.009). While a significant genotype/SSBP association was present in both sexes, their potential mechanisms differed. Women, but not men homozygous risk diplotypes, had significantly greater aldosterone levels than nonrisk diplotypes (5.8±0.4 versus 3.2±0.7 ng/dl; P=0.01; liberal Na+ diet, adjusted). Men, but not women, homozygous risk diplotypes, had significantly reduced renal plasma flow response to Angiotensin II than nonrisk diplotypes (delta 95.2±5.2 versus 122.9±10.2 mL/min per 1.73 m2; P=0.01; liberal Na+ diet, adjusted). The single-nucleotide variants composing the risk diplotype were associated with lower STRN mRNA expression in human tissues (in silico). CONCLUSION: In women, the primary driver of SSBP is increased aldosterone, while in men, it is reduced renal plasma flow responses. Thus, despite a common hypertensive phenotype (SSBP) in both sexes, the specific treatment approaches might differ to increase therapeutic gain and mitigate adverse effects. These genetic- and sex-based observational results require confirmation in a prospective clinical study.


Assuntos
Aldosterona , Hipertensão , Feminino , Humanos , Masculino , Pressão Sanguínea/genética , Nucleotídeos , Estudos Prospectivos , Sódio , Cloreto de Sódio na Dieta
3.
Neuroradiol J ; : 19714009231224429, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38148489

RESUMO

BACKGROUND AND PURPOSE: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. METHODS: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. RESULTS: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. CONCLUSION: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

4.
J Alzheimers Dis ; 95(3): 1133-1145, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37661877

RESUMO

BACKGROUND: Neurofilament light chain (NfL) is a marker of neuronal injury. Perivascular spaces (PVS) visible on magnetic resonance imaging (MRI) represent cerebral small vessel disease (CSVD) but their role as markers of neuronal injury needs further clarification. OBJECTIVE: To relate PVS burden according to brain topography and plasma NfL. METHODS: Framingham Heart Study (FHS) participants with brain MRI and NfL measurements were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) using validated methods and categorized based on counts. A mixed region variable representing high burden PVS in either BG or CSO was assessed. Multivariable linear regression analyses were used to relate PVS burden to log-transformed NfL levels in models adjusted for age, sex, FHS cohort, time between MRI and clinic exam, and image view (model 1), vascular risk factors (model 2), and white matter hyperintensity volume, covert brain infarcts, and cerebral microbleeds (model 3). RESULTS: Among 1,457 participants (68.1±8.5 years, 45% males), NfL levels increased with higher PVS burden. Multivariable analysis showed an association of high PVS burden strictly in BG with NfL (ß= 0.117, 95% CI 0.014-0.221; p = 0.027), but attenuated in model 3. The associations were mainly in participants≥65 years (ß= 0.122, 95% CI 0.015-0.229, p = 0.026), women (ß= 0.156, 95% CI 0.024-0.288, p = 0.021), and APOE ɛ4 non-carriers (ß= 0.140, 95% CI 0.017-0.263, p = 0.026). CONCLUSIONS: The association of strictly BG high PVS burden with NfL suggests a role for PVS as markers of neuroaxonal injury, but our results are hypothesis generating and require further replication.


Assuntos
Doenças de Pequenos Vasos Cerebrais , Filamentos Intermediários , Masculino , Humanos , Feminino , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Gânglios da Base/patologia , Estudos Longitudinais , Doenças de Pequenos Vasos Cerebrais/patologia
5.
FASEB J ; 37(8): e23092, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37482902

RESUMO

Increased endothelin-1 (ET-1) levels in patients with sickle cell disease (SCD) and transgenic mouse models of SCD contribute to disordered hematological, vascular, and inflammatory responses. Mineralocorticoid receptor (MR) activation by aldosterone, a critical component of the Renin-Angiotensin-Aldosterone-System, modulates inflammation and vascular reactivity, partly through increased ET-1 expression. However, the role of MR in SCD remains unclear. We hypothesized that MR blockade in transgenic SCD mice would reduce ET-1 levels, improve hematological parameters, and reduce inflammation. Berkeley SCD (BERK) mice, a model of severe SCD, were randomized to either sickle standard chow or chow containing the MR antagonist (MRA), eplerenone (156 mg/Kg), for 14 days. We found that MRA treatment reduced ET-1 plasma levels (p = .04), improved red cell density gradient profile (D50 ; p < .002), and increased mean corpuscular volume in both erythrocytes (p < .02) and reticulocytes (p < .024). MRA treatment also reduced the activity of the erythroid intermediate-conductance Ca2+ -activated K+ channel - KCa 3.1 (Gardos channel, KCNN4), reduced cardiac levels of mRNAs encoding ET-1, Tumor Necrosis Factor Receptor-1, and protein disulfide isomerase (PDI) (p < .01), and decreased plasma PDI and myeloperoxidase activity. Aldosterone (10-8 M for 24 h in vitro) also increased PDI mRNA levels (p < .01) and activity (p < .003) in EA.hy926 human endothelial cells, in a manner blocked by pre-incubation with the MRA canrenoic acid (1 µM; p < .001). Our results suggest a novel role for MR activation in SCD that may exacerbate SCD pathophysiology and clinical complications.


Assuntos
Anemia Falciforme , Doenças Vasculares , Humanos , Camundongos , Animais , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Células Endoteliais/metabolismo , Aldosterona/metabolismo , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/genética , Modelos Animais de Doenças , Camundongos Transgênicos , Doenças Vasculares/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Endotelina-1/metabolismo , Inflamação/metabolismo
6.
bioRxiv ; 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37333240

RESUMO

The authors have withdrawn their manuscript owing to editing error. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

7.
Front Neurol ; 14: 1080168, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37168667

RESUMO

Cerebral small vessel disease (CSVD) encompasses a broad clinical spectrum united by pathology of the small vessels of the brain. CSVD is commonly identified using brain magnetic resonance imaging with well characterized markers including covert infarcts, white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds. The pathophysiology of CSVD is complex involving genetic determinants, environmental factors, and their interactions. While the role of vascular risk factors in CSVD is well known and its management is pivotal in mitigating the clinical effects, recent research has identified novel genetic factors involved in CSVD. Delineating genetic determinants can promote the understanding of the disease and suggest effective treatments and preventive measures of CSVD at the individual level. Here we review CSVD focusing on recent advances in the genetics of CSVD. The knowledge gained has advanced understanding of the pathophysiology of CSVD, offered promising early results that may improve subtype identification of small vessel strokes, has led to additional identification of mendelian forms of small vessel strokes, and is getting closer to influencing clinical care through pharmacogenetic studies.

8.
JAMA Netw Open ; 6(5): e2313879, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-37195662

RESUMO

Importance: Incident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain. Objective: To evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline. Design, Setting, and Participants: Individual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023. Exposures: Time-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels. Main Outcomes and Measures: The primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Results: A total of 1120 eligible dementia-free individuals with incident stroke were identified; 982 (87.7%) had available covariate data and 138 (12.3%) were excluded for missing covariate data. Of the 982, 480 (48.9%) were female individuals, and 289 (29.4%) were Black individuals. The median age at incident stroke was 74.6 (IQR, 69.1-79.8; range, 44.1-96.4) years. Cumulative mean poststroke SBP and LDL cholesterol levels were not associated with any cognitive outcome. However, after accounting for cumulative mean poststroke SBP and LDL cholesterol levels, higher cumulative mean poststroke glucose level was associated with faster decline in global cognition (-0.04 points/y faster per each 10-mg/dL increase [95% CI, -0.08 to -0.001 points/y]; P = .046) but not executive function or memory. After restricting to 798 participants with apolipoprotein E4 (APOE4) data and controlling for APOE4 and APOE4 × time, higher cumulative mean poststroke glucose level was associated with a faster decline in global cognition in models without and with adjustment for cumulative mean poststroke SBP and LDL cholesterol levels (-0.05 points/y faster per 10-mg/dL increase [95% CI, -0.09 to -0.01 points/y]; P = .01; -0.07 points/y faster per 10-mg/dL increase [95% CI, -0.11 to -0.03 points/y]; P = .002) but not executive function or memory declines. Conclusions and Relevance: In this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.


Assuntos
Disfunção Cognitiva , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Estudos de Coortes , LDL-Colesterol , Apolipoproteína E4 , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/psicologia , Fatores de Risco , Glucose , Sobreviventes
9.
Neurobiol Aging ; 127: 12-22, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37018882

RESUMO

We studied the association between inflammatory biomarkers and magnetic resonance imaging (MRI) visible perivascular spaces (PVS) in Framingham Heart Study participants free of stroke and dementia. PVS in the basal ganglia (BG) and centrum semiovale (CSO) were rated with validated methods and categorized based on counts. A mixed score of high PVS burden in neither, one or both regions was also evaluated. We related biomarkers representing various inflammatory mechanisms to PVS burden using multivariable ordinal logistic regression analysis accounting for vascular risk factors and other MRI markers of cerebral small vessel disease. Among 3604 participants (mean age 58±13 years, 47% males), significant associations were observed for intercellular adhesion molecule1, fibrinogen, osteoprotegerin, and P-selectin in relation to BG PVS, P-selectin for CSO PVS, and tumor necrosis factor receptor 2, osteoprotegerin and cluster of differentiation 40 ligand for mixed topography PVS. Therefore, inflammation may have a role in the pathogenesis of cerebral small vessel disease and perivascular drainage dysfunction represented by PVS, with different and shared inflammatory biomarkers depending on PVS topography.


Assuntos
Doenças de Pequenos Vasos Cerebrais , Osteoprotegerina , Masculino , Humanos , Idoso , Feminino , Selectina-P , Biomarcadores , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Doenças de Pequenos Vasos Cerebrais/patologia
10.
Int J Mol Sci ; 24(7)2023 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37047470

RESUMO

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8-10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12-14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipertensão , Acidente Vascular Cerebral , Animais , Feminino , Ratos , Aldosterona/metabolismo , Angiotensina II/metabolismo , Pressão Sanguínea , Eplerenona/farmacologia , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipertensão/metabolismo , Rim/metabolismo , NG-Nitroarginina Metil Éster , Pravastatina/farmacologia , Ratos Wistar , Receptores de Mineralocorticoides , RNA Mensageiro/metabolismo , Sinvastatina
11.
Front Immunol ; 14: 1124269, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36926339

RESUMO

Major Histocompatibility Complex (MHC) molecules have been proposed to play a role in Sickle Cell Disease (SCD) pathophysiology. Endothelial cells express MHC molecules following exposure to cytokines. SCD is characterized, in part, by vascular endothelial cell activation, increased oxidative stress, sickle cell adhesion, and excess levels of endothelin-1 (ET-1) contributing to vaso-occlusive crises. ET-1 activates endothelial cells, induces oxidative stress and inflammation, and alters erythrocyte volume homeostasis. However, the role of ET-1 on MHC regulation in SCD is unclear. We first studied two sickle transgenic knockout mouse models of moderate to severe disease phenotype, ßS-Antilles and Berkeley (BERK) mice. We observed significant increases in H2-Aa mRNA levels in spleens, lungs, and kidneys from transgenic sickle mice when compared to transgenic knockout mice expressing human hemoglobin A (HbA). Mice treated for 14 days with ET-1 receptor antagonists significantly reduced H2-Aa mRNA levels. We characterized the effect of ET-1 on MHC class II expression in the human endothelial cell line EA.hy926. We observed dose-dependent increases in the expression of MHC class II (HLA-DRA) and MHC transcription factor (CIITA) that were significantly blocked by treatment with BQ788, a selective blocker of ET-1 type B receptors. Chromatin immunoprecipitation studies in EA.hy926 cells showed that ET-1 increased Histone H3 acetylation of the HLA-DRA promoter, an event blocked by BQ788 treatment. These results implicate ET-1 as a novel regulator of MHC class II molecules and suggest that ET-1 receptor blockade represents a promising therapeutic approach to regulate both immune and vascular responses in SCD.


Assuntos
Anemia Falciforme , Células Endoteliais , Camundongos , Humanos , Animais , Receptor de Endotelina A/genética , Cadeias alfa de HLA-DR/genética , Células Endoteliais/metabolismo , Camundongos Transgênicos , Antígenos de Histocompatibilidade Classe II/metabolismo , Complexo Principal de Histocompatibilidade , Camundongos Knockout , RNA Mensageiro/metabolismo
12.
Pediatr Ann ; 52(3): e106-e113, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36881794

RESUMO

Children are at risk of contracting diseases while traveling internationally. Beyond the importance of receiving routine vaccinations, physicians should also discuss with parents the effectiveness of vaccination as a strategy to protect their child against disease before travel. This article (1) explores the universally recommended routine vaccines that are particularly important for children to be up to date before travel (ie, measles, mumps, rubella; hepatitis A and B; polio; meningococcal; coronavirus disease 2019 [COVID-19]; and influenza) and (2) explains the travel-specific vaccination recommendations (ie, dengue, cholera, typhoid, tick-borne encephalitis, yellow fever, Japanese encephalitis, and rabies). Physicians can encourage parents to consult the Centers for Disease Control and Prevention website for travel vaccine recommendations (https://wwwnc.cdc.gov/travel). Children must remain up to date on universally recommended vaccines and receive the appropriate vaccines before international travel to prevent serious illness and limit the spread of diseases in the United States. [Pediatr Ann. 2023;52(3):e106-e113.].


Assuntos
COVID-19 , Vacinas contra Influenza , Influenza Humana , Estados Unidos , Criança , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinação , Centers for Disease Control and Prevention, U.S.
14.
Pediatr Ann ; 52(3): e83-e88, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36881800

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has had a large effect on the pediatric population, with 16,000,000 cases and counting. Currently, there are two messenger RNA (mRNA)-based and a single adjuvanted, protein-based COVID-19 vaccine approved for use in children and adolescents in the United States. Multiple studies have highlighted that these vaccines are safe for use in children and adolescents and are effective at reducing COVID-19 infection and complications. Given the risk of the SARS-CoV-2 virus to the pediatric population and ongoing global viral transmission, it is advised that providers emphasize the value of COVID-19 vaccination for children and adolescents. [Pediatr Ann. 2023;52(3):e83-e88.].


Assuntos
Vacinas contra COVID-19 , COVID-19 , Criança , Adolescente , Humanos , Vacinas contra COVID-19/efeitos adversos , COVID-19/epidemiologia , COVID-19/prevenção & controle , SARS-CoV-2 , Pandemias , Vacinação
15.
Alzheimers Dement ; 19(2): 621-631, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35522830

RESUMO

INTRODUCTION: We investigated cross-sectional associations between the Dietary Inflammatory Index (DII) and measures of brain volume and cerebral small vessel disease among participants of the Framingham Heart Study Offspring cohort. METHODS: A total of 1897 participants (mean ± standard deviation, age 62±9) completed Food Frequency Questionnaires and brain magnetic resonance imaging (MRI). RESULTS: Higher (pro-inflammatory) DII scores, averaged across a maximum of three time points, were associated with smaller total brain volume (beta ± standard error: -0.16 ± 0.03; P < .0001) after adjustment for demographic, clinical, and lifestyle covariates. In addition, higher DII scores were associated with smaller total gray matter volume (-0.08 ± 0.03; P = .003) and larger lateral ventricular volume (0.04 ± 0.02; P = .03). No associations were observed with other brain MRI measures. DISCUSSION: Our findings showed associations between higher DII scores and global brain MRI measures. As we are one of the first groups to report on the associations between higher DII scores and brain volume, replication is needed to confirm our findings.


Assuntos
Envelhecimento , Encéfalo , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Transversais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Inflamação
16.
J Endocrinol ; 256(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36327153

RESUMO

Biologic sex influences the development of cardiovascular disease and modifies aldosterone (ALDO) and blood pressure (BP) phenotypes: females secrete more ALDO, and their adrenal glomerulosa cell is more sensitive to stimulation. Lysine-specific demethylase 1 (LSD1) variants in Africans and LSD1 deficiency in mice are associated with BP and/or ALDO phenotypes. This study, in 18- and 40-week-old wild type (WT) and LSD1+/- mice, was designed to determine whether (1) sex modifies ALDO biosynthetic enzymes; (2) LSD1 deficiency disrupts the effect of sex on these enzymes; (3) within each genotype, there is a positive relationship between ALDO biosynthesis (proximate phenotype), plasma ALDO (intermediate phenotype) and BP levels (distant phenotype); and (4) sex and LSD1 genotype interact on these phenotypes. In WT mice, female sex increases the expression of early enzymes in ALDO biosynthesis but not ALDO levels or systolic blood pressure (SBP). However, enzyme expressions are shifted downward in LSD1+/- females vs males, so that early enzyme levels are similar but the late enzymes are substantially lower. In both age groups, LSD1 deficiency modifies the adrenal enzyme expressions, circulating ALDO levels, and SBP in a sex-specific manner. Finally, significant sex/LSD1 genotype interactions modulate the three phenotypes in mice. In conclusion, biologic sex in mice interacts with LSD1 deficiency to modify several phenotypes: (1) proximal (ALDO biosynthetic enzymes); (2) intermediate (circulating ALDO); and (3) distant (SBP). These results provide entry to better understand the roles of biological sex and LSD1 in (1) hypertension heterogeneity and (2) providing more personalized treatment.


Assuntos
Hipertensão , Lisina , Masculino , Feminino , Camundongos , Animais , Lisina/metabolismo , Lisina/farmacologia , Aldosterona/metabolismo , Pressão Sanguínea , Hipertensão/metabolismo , Zona Glomerulosa/metabolismo
17.
FASEB J ; 36(12): e22638, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36331552

RESUMO

Painful crises in sickle cell disease (SCD) are associated with increased plasma cytokines levels, including endothelin-1 (ET-1). Reduced red cell magnesium content, mediated in part by increased Na+ /Mg2+ exchanger (NME) activity, contributes to erythrocyte K+ loss, dehydration and sickling in SCD. However, the relationship between ET-1 and the NME in SCD has remained unexamined. We observed increased NME activity in sickle red cells incubated in the presence of 500 nM ET-1. Deoxygenation of sickle red cells, in contrast, led to decreased red cell NME activity and cellular dehydration that was reversed by the NME inhibitor, imipramine. Increased NME activity in sickle red cells was significantly blocked by pre-incubation with 100 nM BQ788, a selective blocker of ET-1 type B receptors. These results suggest an important role for ET-1 and for cellular magnesium homeostasis in SCD. Consistent with these results, we observed increased NME activity in sickle red cells of three mouse models of sickle cell disease greater than that in red cells of C57BL/J6 mice. In vivo treatment of BERK sickle transgenic mice with ET-1 receptor antagonists reduced red cell NME activity. Our results suggest that ET-1 receptor blockade may be a promising therapeutic approach to control erythrocyte volume and magnesium homeostasis in SCD and may thus attenuate or retard the associated chronic inflammatory and vascular complications of SCD.


Assuntos
Anemia Falciforme , Endotelina-1 , Camundongos , Animais , Endotelina-1/metabolismo , Magnésio/metabolismo , Desidratação/metabolismo , Camundongos Endogâmicos C57BL , Eritrócitos/metabolismo , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Sódio/metabolismo , Homeostase , Receptor de Endotelina B/metabolismo , Camundongos Transgênicos
18.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232479

RESUMO

Oxidative stress plays an important role in vascular complications observed in patients with obesity and Type 2 Diabetes (T2D). Xanthine oxidase (XO) breaks down purine nucleotides into uric acid and contributes to the production of reactive oxygen species (ROS). However, the relationship between XO activity and glucose homeostasis in T2D subjects with obesity is unclear. We hypothesized that disordered glucose levels are associated with serum XO activity in overweight women and men with T2D and without hyperuricemia. We studied serum XO activity in women and men with and without T2D. Our results show that serum XO activity was greater in T2D patients with body mass index (BMI) ≥ 25 kg/m2 than in those with BMI < 25 kg/m2 (p < 0.0001). Sex-based comparative analyses of overweight T2D patients showed that serum XO activity correlated with homeostasis model assessment of ß-cell function (HOMA-ß), fasting plasma glucose (FPG), and hemoglobin A1C in overweight T2D women but not in overweight T2D men. In addition, as compared to overweight T2D men, women had higher high-sensitivity C-reactive protein (hs-CRP) levels. However, overweight T2D men had higher XO activity and uric acid levels than women. Our results suggest that XO activity is higher in overweight T2D patients, especially in men, but is more sensitive to disordered glucose levels in overweight women with T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Sobrepeso , Glicemia/análise , Proteína C-Reativa/metabolismo , Diabetes Mellitus Tipo 2/complicações , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Obesidade/complicações , Sobrepeso/complicações , Nucleotídeos de Purina , Espécies Reativas de Oxigênio/metabolismo , Ácido Úrico , Xantina Oxidase/metabolismo
19.
Dement Geriatr Cogn Disord ; 51(5): 377-385, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36316004

RESUMO

BACKGROUND: Extracranial carotid atherosclerosis has been variably associated with dementia. Prior studies have focused on the association of carotid intima media thickness or carotid stenosis; however, there is evidence that carotid plaque may contribute to dementia, perhaps via microembolic phenomena. OBJECTIVES: We sought to evaluate the role of carotid plaque in contributing to cognitive impairment by performing a systematic review and meta-analysis to summarize the association between extracranial carotid plaque and cognitive dysfunction and dementia. METHODS: We performed a comprehensive literature search evaluating the association of extracranial carotid plaque with cognition. We included studies measuring carotid plaque on ultrasound, computed tomography, or MR and also evaluated cognition through neuropsychological testing. Meta-analyses with assessment of study heterogeneity and publication bias were performed. Results were presented in a forest plot and summarized using a random-effects model. RESULTS: After screening 1,674 studies, we included 40 for systematic review and 16 and 7 studies for two meta-analyses with a total of 19,029 and 27,325 patients, respectively. We found a positive relationship between the presence of extracranial carotid plaque and cognitive dysfunction with a pooled random-effects odds ratio (OR) of 1.83 (95% CI, 1.50, 2.24) and a pooled random-effects hazard ratio (HR) of 1.47 (95% CI, 1.15, 1.89), respectively. A sensitivity analysis of only longitudinal studies found a persistent positive association. Measures of heterogeneity showed moderate heterogeneity in each meta-analysis, respectively (I-squared statistic = 57% and 70%). CONCLUSION: The presence of extracranial carotid plaque is significantly associated with cognitive dysfunction and dementia in both cross-sectional and longitudinal analyses. After further confirmation, our results support carotid plaque being a potentially modifiable risk factor in the development of dementia.


Assuntos
Estenose das Carótidas , Disfunção Cognitiva , Demência , Placa Aterosclerótica , Humanos , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Estudos Transversais , Disfunção Cognitiva/complicações , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico por imagem , Fatores de Risco , Demência/complicações
20.
Sleep Med ; 100: 558-564, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36308914

RESUMO

BACKGROUND: While healthy sleep is suggested to promote glymphatic clearance in the brain, poorer sleep may be associated with higher enlarged perivascular spaces (ePVS) burden, potentially representing impaired perivascular drainage. This study aims to evaluate the association between ePVS burden and polysomnographic sleep characteristics in a large community-based sample. METHODS: 552 dementia and stroke-free Framingham Heart Study participants (age: 58.6 ± 8.9 years; 50.4% men) underwent a full-night in-home polysomnography. Three years later on average, participants underwent a brain MRI. ePVS were rated in the basal ganglia and centrum semiovale, and dichotomized as low burden (<20 counts, grades 1 and 2) or high burden (>20 counts, grades 3 and 4). Logistic regression analyses relating sleep variables to subsequent ePVS burden were used, adjusted for age, sex, time interval between polysomnography and MRI, ApoE ε4 allele carrier status, hypertension, and smoking. RESULTS: Longer N1 sleep and shorter N3 sleep duration were associated with higher ePVS burden in the centrum semiovale. When stratifying these associations by subpopulations, longer N1 sleep duration with ePVS burden was observed especially in older individuals and hypertensive participants. Associations between ePVS burden and other sleep characteristics such as total sleep time and REM sleep duration varied according to ApoE ε4 allele carrier status. CONCLUSIONS: Lighter sleep, as characterized by longer N1 sleep and shorter slow-wave sleep, is associated with higher ePVS burden. These findings suggest that sleep architecture may be involved in glymphatic clearance and cerebral small vessel disease, which could be an important biological link between sleep and dementia risk.


Assuntos
Doenças de Pequenos Vasos Cerebrais , Demência , Hipertensão , Pessoa de Meia-Idade , Idoso , Masculino , Humanos , Feminino , Apolipoproteína E4 , Doenças de Pequenos Vasos Cerebrais/complicações , Gânglios da Base , Imageamento por Ressonância Magnética , Hipertensão/complicações , Sono , Demência/complicações
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