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1.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360587

RESUMO

In the present study, we analyzed the activity of several aminopeptidases (angiotensinases) involved in the metabolism of various angiotensin peptides, in pituitary and adrenal glands of untreated Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) or treated with the antihypertensive drugs captopril and propranolol or with the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). Intra- and inter-gland correlations between angiotensinase activities were also calculated. Membrane-bound alanyl-, cystinyl-, and glutamyl-aminopeptidase activities were determined fluorometrically using aminoacyl-ß-naphthylamide as substrates. Depending on the type of angiotensinase analyzed, the results reflect a complex picture showing substantial differences between glands, strains, and treatments. Alanyl-aminopeptidase responsible for the metabolism of Ang III to Ang IV appears to be the most active angiotensinase in both pituitary and adrenals of WKY and particularly in SHR. Independently of treatment, most positive correlations are observed in the pituitary gland of WKY whereas such positive correlations are predominant in adrenals of SHR. Negative inter-gland correlations were observed in control SHR and L-NAME treated WKY. Positive inter-gland correlations were observed in captopril-treated SHR and propranolol-treated WKY. These results may reflect additional mechanisms for increasing or decreasing systolic blood pressure in WKY or SHR.


Assuntos
Glândulas Suprarrenais/metabolismo , Anti-Hipertensivos/farmacologia , Endopeptidases/metabolismo , Hipertensão/metabolismo , Hipotensão/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Hipófise/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Captopril/farmacologia , Endopeptidases/genética , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Hipotensão/tratamento farmacológico , Hipotensão/patologia , Masculino , Hipófise/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
2.
J R Soc Interface ; 18(180): 20210336, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34314650

RESUMO

Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.


Assuntos
Túnica Adventícia , Hipertensão , Túnica Adventícia/patologia , Animais , Aorta/patologia , Aorta Torácica/patologia , Modelos Animais de Doenças , Fibrose , Hipertensão/patologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/patologia
3.
Life Sci ; 283: 119855, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34314734

RESUMO

AIMS: Aging is an obvious risk factor for detrusor underactivity. We investigated the effects of aging on bladder function in spontaneously hypertensive rats. MAIN METHODS: Male spontaneously hypertensive rats and Wistar Kyoto rats (used as normotensive controls) at the ages of 18, 36, 54, or 72 weeks were used. Bladder weight, blood pressure, bladder blood flow, and urodynamic and renal parameters were measured. Additionally, detrusor thickness and renal histology were evaluated. KEY FINDINGS: In spontaneously hypertensive rats, significant increases were observed in bladder weight/body weight ratio, blood pressure, detrusor thickness, intercontraction interval, urine output, serum creatinine, and renal glomerular and tubular scores, and decreases in bladder blood flow and urine osmolality at 72 weeks as compared to those at 18 weeks. In spontaneously hypertensive rats, significant increases were observed in single voided volume, post voiding residual urine volume, and bladder capacity, with decrease in voiding efficiency were observed at 54 or 72 weeks than at 18 weeks. However, there were no significant differences in blood pressure, urodynamic and renal parameters, detrusor thickness and renal histology among Wistar Kyoto rats of different ages. SIGNIFICANCE: In spontaneously hypertensive rats, aging induces significant increases in blood pressure, single voided volume, post voiding residual urine volume, intercontraction intervals and urine output, and decreases in voiding efficiency and bladder blood flow indicative of detrusor underactivity. Aging-related severe hypertension could induce voiding dysfunction such as detrusor underactivity via severe bladder ischemia and polyuria. Aged spontaneously hypertensive rats may be useful animal models for detrusor underactivity.


Assuntos
Envelhecimento/metabolismo , Hipertensão , Bexiga Inativa , Bexiga Urinária , Envelhecimento/patologia , Animais , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Índice de Gravidade de Doença , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Bexiga Inativa/etiologia , Bexiga Inativa/metabolismo , Bexiga Inativa/patologia , Bexiga Inativa/fisiopatologia
4.
Cardiovasc Pathol ; 54: 107370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34273507

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is commonly associated with myocardial injury and heart failure. The pathophysiology behind this phenomenon remains unclear, with many diverse and multifaceted hypotheses. To contribute to this understanding, we describe the underlying cardiac findings in fifty patients who died with coronavirus disease 2019 (COVID-19). METHODS: Included were autopsies performed on patients with a positive SARS-CoV-2 reverse-transcriptase-polymerase-chain reaction test from the index hospitalization. In the case of out-of-hospital death, patients were included if post-mortem testing was positive. Complete autopsies were performed according to a COVID-19 safety protocol, and all patients underwent both macroscopic and microscopic examination. If available, laboratory findings and echocardiograms were reported. RESULTS: The median age of the decedents was 63.5 years. The most common comorbidities included hypertension (90.0%), diabetes (56.0%) and obesity (50.0%). Lymphocytic inflammatory infiltrates in the heart were present in eight (16.0%) patients, with focal myocarditis present in two (4.0%) patients. Acute myocardial ischemia was observed in eight (16.0%) patients. The most common findings were myocardial fibrosis (80.0%), hypertrophy (72.0%), and microthrombi (66.0%). The most common causes of death were COVID-19 pneumonia in 18 (36.0%), COVID-19 pneumonia with bacterial superinfection in 12 (24.0%), and COVID-19 pneumonia with pulmonary embolism in 10 (20.0%) patients. CONCLUSIONS: Cardiovascular comorbidities were prevalent, and pathologic changes associated with hypertensive and atherosclerotic cardiovascular disease were the most common findings. Despite markedly elevated inflammatory markers and cardiac enzymes, few patients exhibited inflammatory infiltrates or necrosis within cardiac myocytes. A unifying pathophysiologic mechanism behind myocardial injury in COVID-19 remains elusive, and additional autopsy studies are needed.


Assuntos
COVID-19/patologia , Cardiopatias/patologia , Miocárdio/patologia , SARS-CoV-2/patogenicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/mortalidade , Aterosclerose/patologia , Autopsia , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/virologia , Comorbidade , Feminino , Cardiopatias/imunologia , Cardiopatias/mortalidade , Cardiopatias/virologia , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/mortalidade , Hipertensão/patologia , Mediadores da Inflamação/análise , Masculino , Pessoa de Meia-Idade , Miocárdio/imunologia , Necrose , SARS-CoV-2/imunologia , Regulação para Cima
5.
Maturitas ; 150: 22-29, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34274072

RESUMO

OBJECTIVES: While it has been reported that women with uterine fibroids or endometriosis are commonly overweight and hypertensive, the association between non-malignant gynecological diseases and the risk of hypertension has been little studied prospectively. The aim of this study was to investigate in a large French cohort of women whether a history of hysterectomy, uterine fibroids, or endometriosis was prospectively related to an increased risk of incident hypertension. STUDY DESIGN: We analyzed 50,286 women from the E3N cohort who were free of hypertension at baseline, with a median follow-up of 16.4 years. MAIN OUTCOME MEASURES: Gynecological diseases were based on self-report. Cox proportional hazards models with age as the timescale were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Covariates included smoking status, body mass index (BMI), physical activity, and hormonal factors. RESULTS: A total of 12,073 women (24%) developed hypertension during follow-up. Women with a history of hysterectomy had an increased risk of incident hypertension, which persisted after adjustment for potential confounding factors (adjusted HR=1.18, 95% CI 1.12-1.24). Risk was similar in women with hysterectomy with or without oophorectomy. Risk of hypertension was higher in women with a history of endometriosis (HRendometriosis 1.19, 95%CI 1.11-1.22) or uterine fibroids (HRfibroids 1.18, 95%CI 1.13-1.22), irrespective of hysterectomy. Associations were similar after further adjustment for BMI. CONCLUSIONS: Hysterectomy and non-malignant gynecological diseases were associated with an increased risk of hypertension in this large prospective study. Women with these conditions may benefit from blood pressure monitoring. ClinicalTrials.gov identifier: NCT03285230.


Assuntos
Índice de Massa Corporal , Doenças dos Genitais Femininos/cirurgia , Hipertensão/etiologia , Histerectomia/efeitos adversos , Ovariectomia/efeitos adversos , Adulto , Idoso , Feminino , França/epidemiologia , Humanos , Hipertensão/epidemiologia , Hipertensão/patologia , Incidência , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
6.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207980

RESUMO

Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular-coerulear excitatory interactions in prenatally undernourished young-adult rats.


Assuntos
Hipertensão/patologia , Hipotálamo/metabolismo , Desnutrição/complicações , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Feminino , Frequência Cardíaca , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos
7.
Biomed Pharmacother ; 139: 111668, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243630

RESUMO

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.


Assuntos
Aterosclerose/patologia , Dieta/efeitos adversos , Hipertensão/patologia , Síndrome Metabólica/patologia , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipertensão/sangue , Hipertensão/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Triglicerídeos/sangue
8.
Diabetes Metab Syndr ; 15(4): 102148, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34186349

RESUMO

BACKGROUND: Socio-demographics and comorbidities are involved in determining the severity and fatality in patients with COVID-19 suggested by studies in various countries, but study in Bangladesh is insufficient. AIMS: We designed the study to evaluate the association of sociodemographic and comorbidities with the prognosis of adverse health outcomes in patients with COVID-19 in Bangladesh. METHODS: A multivariate retrospective cohort study was conducted on data from 966 RT-PCR positive patients from eight divisions during December 13, 2020, to February 13, 2021. Variables included sociodemographic, comorbidities, symptoms, Charlson comorbidity index (CCI) and access to health facilities. Major outcome was fatality. Secondary outcomes included hospitalization, duration of hospital stay, requirement of mechanical ventilation and severity. RESULTS: Male (65.8%, 636 of 966) was predominant and mean age was 39.8 ± 12.6 years. Fever (79%), dry cough (55%), and loss of test/smell (51%) were frequent and 74% patients had >3 symptoms. Fatality was recorded in 10.5% patients. Comorbidities were found in 44% patients. Hypertension (21.5%) diabetes (14.6%), and cardiovascular diseases (11.3%) were most prevalent. Age >60 years (OR: 4.83, 95% CI: 2.45-6.49), and CCI >3 (OR: 5.48, 95% CI: 3.95-7.24) were predictors of hospitalizations. CCI >4 (aOR: 3.41, 95% CI: 2.57-6.09) was predictor of severity. Age >60 years (aOR: 3.77, 95% CI: 1.07-6.34), >3 symptoms (aOR: 2.14, 95% CI: 0.97-4.91) and CCI >3 vs. CCI <3 (aOR: 5.23, 95% CI: 3.77-8.09) were independently associated with fatality. CONCLUSIONS: Increased age, >3 symptoms, increasing comorbidities, higher CCI were associated with increased hospitalization, severity and fatality in patients with COVID-19.


Assuntos
COVID-19/complicações , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus/mortalidade , Hospitalização/estatística & dados numéricos , Hipertensão/mortalidade , SARS-CoV-2/isolamento & purificação , Adolescente , Adulto , Fatores Etários , Idoso , Bangladesh/epidemiologia , COVID-19/transmissão , COVID-19/virologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/virologia , Criança , Pré-Escolar , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Diabetes Mellitus/virologia , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/patologia , Hipertensão/virologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
9.
FASEB J ; 35(7): e21678, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34133045

RESUMO

Hypertension is associated with excessive reactive oxygen species (ROS) production in vascular cells. Mitochondria undergo fusion and fission, a process playing a role in mitochondrial function. OPA1 is essential for mitochondrial fusion. Loss of OPA1 is associated with ROS production and cell dysfunction. We hypothesized that mitochondria fusion could reduce oxidative stress that defect in fusion would exacerbate hypertension. Using (a) Opa1 haploinsufficiency in isolated resistance arteries from Opa1+/- mice, (b) primary vascular cells from Opa1+/- mice, and (c) RNA interference experiments with siRNA against Opa1 in vascular cells, we investigated the role of mitochondria fusion in hypertension. In hypertension, Opa1 haploinsufficiency induced altered mitochondrial cristae structure both in vascular smooth muscle and endothelial cells but did not modify protein level of long and short forms of OPA1. In addition, we demonstrated an increase of mitochondrial ROS production, associated with a decrease of superoxide dismutase 1 protein expression. We also observed an increase of apoptosis in vascular cells and a decreased VSMCs proliferation. Blood pressure, vascular contractility, as well as endothelium-dependent and -independent relaxation were similar in Opa1+/- , WT, L-NAME-treated Opa1+/- and WT mice. Nevertheless, chronic NO-synthase inhibition with L-NAME induced a greater hypertension in Opa1+/- than in WT mice without compensatory arterial wall hypertrophy. This was associated with a stronger reduction in endothelium-dependent relaxation due to excessive ROS production. Our results highlight the protective role of mitochondria fusion in the vasculature during hypertension by limiting mitochondria ROS production.


Assuntos
GTP Fosfo-Hidrolases/fisiologia , Hipertensão/prevenção & controle , Dinâmica Mitocondrial , Substâncias Protetoras/administração & dosagem , Animais , Apoptose , Inibidores Enzimáticos/toxicidade , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NG-Nitroarginina Metil Éster/toxicidade , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
10.
Kidney Blood Press Res ; 46(3): 362-376, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34077925

RESUMO

OBJECTIVE: Complement deposition is prevalent in kidney biopsies of patients with arterial hypertension and hypertensive nephropathy, but an association of hypertension and complement deposition or involvement of complement in the pathogenesis of hypertensive nephropathy has not been shown to date. METHODS: In this study, we analyzed complement C1q and C3c deposition in a rat model of overload and hypertension by subtotal nephrectomy (SNX) and in archival human renal biopsies from 217 patients with known hypertension and 91 control patients with no history of hypertension using semiquantitative scoring of C1q and C3c immunohistochemistry and correlation with parameters of renal function. To address whether complement was only passively deposited or actively expressed by renal cells, C1q and C3 mRNA expression were additionally analyzed. RESULTS: Glomerular C1q and C3c complement deposition were significantly higher in kidneys of hypertensive SNX rats and hypertensive compared to nonhypertensive patients. Mean arterial blood pressure (BP) in SNX rats correlated well with the amount of glomerular C1q and C3c deposition and with left ventricular weight, as an indirect parameter of high BP. Quantitative mRNA analysis showed that C3 was not only deposited but also actively produced by glomerular cells of hypertensive SNX rats and in human renal biopsies. Of note, in patients CKD-stage correlated significantly with the intensity of glomerular C3c staining, but not with that of C1q. CONCLUSION: Renal complement deposition correlated with experimental hypertension as well as the presence of hypertension in a variety of renal diseases. To answer the question, if and how exactly renal complement is causative for the pathogenesis of arterial hypertension in men, further studies are needed.


Assuntos
Complemento C1q/análise , Complemento C3c/análise , Hipertensão/patologia , Nefropatias/patologia , Rim/patologia , Adulto , Idoso , Animais , Biópsia , Feminino , Humanos , Hipertensão/complicações , Nefropatias/complicações , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Ratos
11.
Maturitas ; 149: 26-33, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34134887

RESUMO

OBJECTIVES: To assess the vitamin D levels, prevalence of vitamin D deficiency and genotypes of Fok-I, Bsm-I, Apa-I and Taq-I polymorphisms in the VDR gene and to determine whether vitamin D deficiency and VDR gene variants are associated with blood pressure levels and systemic arterial hypertension as defined by the 2017 ACC/AHA criteria. STUDY DESIGN: A cross-sectional study of biobanked blood samples from 339 postmenopausal women. MAIN OUTCOME MEASURES: Blood pressure strata were defined according to the 2017 ACC/AHA cutoffs. Circulating 25(OH)D levels were considered deficient if <20 ng/mL. RESULTS: Mean serum total 25(OH)D levels were 22.99 ± 8.54 ng/mL, and 40.1% of participants were deficient in vitamin D. Overall, 7.7% had elevated blood pressure, 36.6% had stage 1 and 37.8% had stage 2 hypertension. Mean total (p = 0.014) and free 25(OH)D levels (p = 0.029) were lower in women with stage 2 hypertension than in those with normal blood pressure. A higher prevalence rate of stage 2 hypertension was associated with age (PR 1.058; 95%CI 1.033-1.083; p < 0.001), BMI (PR 1.046; 95%CI 1.025-1.068; p < 0.001), vitamin D deficiency (PR 1.333; 95%CI 1.016-1.749; p = 0.038) and Taq-I polymorphism (PR 1.764; 95%CI 1.030-3.019; p = 0.039). Women with vitamin D deficiency and the AA+AG genotype of Taq-I polymorphism were 33% and 76% more likely to have stage 2 hypertension, respectively, but these associations lost significance when adjusted for age and BMI. CONCLUSION: The results suggest that vitamin D deficiency and Taq-I polymorphism are associated with stage 2 hypertension, depending on age and BMI, in postmenopausal women.


Assuntos
Hipertensão/etiologia , Polimorfismo Genético , Pós-Menopausa , Receptores de Calcitriol/genética , Deficiência de Vitamina D/complicações , Adulto , Idoso , American Heart Association , Brasil/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/patologia , Pessoa de Meia-Idade , Prevalência , Estados Unidos , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Vitaminas/sangue
12.
Nat Commun ; 12(1): 2783, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986294

RESUMO

Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.


Assuntos
Proteínas CLOCK/genética , Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Cardiopatias/patologia , Monócitos/metabolismo , Insuficiência Renal Crônica/patologia , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/metabolismo , Células Cultivadas , Ritmo Circadiano/genética , Citocinas/biossíntese , Fibrose/patologia , Hipertensão/genética , Hipertensão/patologia , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Receptores Acoplados a Proteínas G/metabolismo
13.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33803946

RESUMO

A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive hypertension as key switches of intracellular signaling. Focusing on Rho, high salt intake in the central nervous system increases sodium concentrations of cerebrospinal fluid in salt-sensitive subjects via Rho/Rho kinase and renin-angiotensin system activation and causes increased brain salt sensitivity and sympathetic nerve outflow in BP control centers. In vascular smooth muscle cells, Rho-guanine nucleotide exchange factors and Rho determine sensitivity to vasoconstrictors such as angiotensin II (Ang II), and facilitate vasoconstriction via G-protein and Wnt pathways, leading to increased vascular resistance, including in the renal arteries, in salt-sensitive subjects with high salt intake. In the vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) production and function, and high salt amounts further augment Rho activity via asymmetric dimethylarginine, an endogenous inhibitor of NO synthetase, causing aberrant relaxation and increased vascular tone. Rho-associated mechanisms are deeply involved in the development of salt-sensitive hypertension, and their further elucidation can help in developing effective protection and new therapies.


Assuntos
Hipertensão/genética , Vasoconstrição/genética , Quinases Associadas a rho/genética , Angiotensina II/genética , Pressão Sanguínea/efeitos dos fármacos , Humanos , Hipertensão/induzido quimicamente , Hipertensão/patologia , Óxido Nítrico/genética , Óxido Nítrico Sintase/genética , Cloreto de Sódio na Dieta/efeitos adversos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo
14.
J Biol Chem ; 296: 100667, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33864813

RESUMO

The epoxyeicosatrienoic acid (EET) exerts beneficial effects on insulin resistance and/or hypertension. EETs could be readily converted to less biological active diols by soluble epoxide hydrolase (sEH). However, whether sEH inhibition can ameliorate the comorbidities of insulin resistance and hypertension and the underlying mechanisms of this relationship are unclear. In this study, C57BL/6 mice were rendered hypertensive and insulin resistant through a high-fat and high-salt (HF-HS) diet. The sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), was used to treat mice (1 mg/kg/day) for 8 weeks, followed by analysis of metabolic parameters. The expression of sEH and the sodium-glucose cotransporter 2 (SGLT2) was markedly upregulated in the kidneys of mice fed an HF-HS diet. We found that TPPU administration increased kidney EET levels, improved insulin resistance, and reduced hypertension. Furthermore, TPPU treatment prevented upregulation of SGLT2 and the associated increased urine volume and the excretion of urine glucose and urine sodium. Importantly, TPPU alleviated renal inflammation. In vitro, human renal proximal tubule epithelial cells (HK-2 cells) were used to further investigate the underlying mechanism. We observed that 14,15-EET or sEH knockdown or inhibition prevented the upregulation of SGLT2 upon treatment with palmitic acid or NaCl by inhibiting the inhibitory kappa B kinase α/ß/NF-κB signaling pathway. In conclusion, sEH inhibition by TPPU alleviated insulin resistance and hypertension induced by an HF-HS diet in mice. The increased urine excretion of glucose and sodium was mediated by decreased renal SGLT2 expression because of inactivation of the inhibitory kappa B kinase α/ß/NF-κB-induced inflammatory response.


Assuntos
Epóxido Hidrolases/antagonistas & inibidores , Regulação da Expressão Gênica , Hipertensão/prevenção & controle , Resistência à Insulina , Rim/metabolismo , Doenças Metabólicas/prevenção & controle , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Regulação para Baixo , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/patologia , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Transportador 2 de Glucose-Sódio/genética
15.
Blood Press ; 30(3): 196-204, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33792450

RESUMO

BACKGROUND AND AIMS: High blood pressure is the heritable risk factor for cardiovascular diseases. We investigated whether the presence of familial genetic and environmental risk factors are associated with increased risk of high blood pressure. METHODS: A total of 4,559 individuals from 401 families were included in this study. Familial aggregation analysis was carried out on systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI) and waist circumference (WC), and heritability was estimated for SBP and DBP. The association between familial risk factors and blood pressure traits including, incidence of hypertension, SBP and DBP was estimated separately using regression-based two-level Haseman-Elston (HE) method, with individual and familial BMI and WC as environmental exposures and familial genetic profile of known variants as genetic risk factors in 210 index families (≥2 hypertensive cases). Models were adjusted for the two nested sets of covariates. RESULTS: During a follow-up of 15 years, the SBP, DBP, BMI and WC were highly correlated in inter class of mother-offspring and intraclass of sister-sister with heritability of 30 and 25% for DBP and SBP, respectively. Among index families, those whose members with higher familial BMI or WC had significantly increased risk of hypertension and consistent, strong signals of rs2493134 (AGT) linked with SBP and DBP, rs976683 (NLGN1) linked with SBP and HTN, and epistasis of rs2021783 (TNXB) and known genetic variants linked with all blood pressure traits. CONCLUSIONS: Findings from this study show that familial genetic and environmental risk profile increase risk for high blood pressure beyond the effect of the individuals' own risk factors.


Assuntos
Pressão Sanguínea/genética , Índice de Massa Corporal , Exposição Ambiental/efeitos adversos , Variação Genética , Hipertensão , Modelos Cardiovasculares , Modelos Genéticos , Característica Quantitativa Herdável , Circunferência da Cintura , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Tenascina/genética , Tenascina/metabolismo
16.
Qual Life Res ; 30(7): 2045-2060, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33821418

RESUMO

PURPOSE: The purpose of this study was to compare the measurement properties of two versions of EQ-5D (i.e.EQ-5D-3L and EQ-5D-5L) in hypertensive patients in rural China. METHODS: A cross-sectional survey was carried out in hypertensive patients in rural China. We compared the ceiling effects, redistribution properties, informativity, known-groups validity, and relative efficiency of the 3L and 5L and examined their agreement. RESULTS: A total of 11,412 patients were enrolled in our study. The mean EQ-5D index score was 0.84 (SD 0.21) according to the 5L and 0.86 (SD 0.17) according to the 3L. A good agreement was observed between the 3L and 5L. The overall ceiling effect decreased from 46.4% (3L) to 29.4% (5L). The Shannon index, H' improved in all dimensions when used 5L. When used 3L, the median responses of all groups were consistent with 5L across the three dimensions of 'mobility', 'self-care', 'usual activities', while the median responses were inconsistent for the 'pain/discomfort' and 'anxiety/depression' dimensions. The 3L performed better in eight comorbidities in terms of F-statistics and six comorbidities in terms of the area under the receiver operating characteristic curves (AUROCs). The 5L performed better both in terms of the F-statistics and AUROCs in age, education level, anti-hypertensive medication use. CONCLUSION: Taking all comparisons into account, we recommend the EQ-5D-5L for use in patients with hypertension in rural China.


Assuntos
Hipertensão/epidemiologia , Psicometria/métodos , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Estudos Transversais , Feminino , Humanos , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , População Rural , Inquéritos e Questionários , Adulto Jovem
17.
Aging (Albany NY) ; 13(8): 11610-11628, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33885378

RESUMO

Chronic angiotensin II (Ang II) stimulation induces vascular smooth muscle cell (VSMC) senescence, and circRNAs and members of the ILF3 family are implicated in cellular senescence, but the mechanism underlying regulation of circRNAs and ILF3 by Ang II in VSMCs remains poorly understood. Here, a model of Ang II-induced VSMC senescence and the renal artery of hypertensive patients were used to investigate the roles and mechanisms of circACTA2 and ILF3 in VSMC senescence. We show that circACTA2 expression was elevated in Ang II-stimulated VSMCs and in the vascular walls of hypertensive patients. circACTA2 knockdown largely abrogated Ang II-induced VSMC senescence as shown by decreased p21 expression and increased CDK4 expression as well as by decreased SA ß-gal-positive cells. Oligo pull-down and RIP assays revealed that both circACTA2 and CDK4 mRNA could bind with ILF3, and Ang II facilitated circACTA2 association with ILF3 and attenuated ILF3 interaction with CDK4 mRNA. Mechanistically, increased circACTA2 by Ang II reduced ILF3 association with CDK4 mRNA by competing with CDK4 mRNA to bind to ILF3, which decreases CDK4 mRNA stability and protein expression, thus leading to Ang II-induced VSMC senescence. Targeting the circACTA2-ILF3-CDK4 axis may provide a novel therapeutic strategy for VSMC senescence-associated cardiovascular diseases.


Assuntos
Senescência Celular/genética , Quinase 4 Dependente de Ciclina/genética , Hipertensão/patologia , Proteínas do Fator Nuclear 90/metabolismo , RNA Circular/metabolismo , Angiotensina II/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Miócitos de Músculo Liso/patologia , RNA Circular/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo
18.
Iran J Allergy Asthma Immunol ; 20(2): 140-146, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33904672

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic in Iran is part of the worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The present study aimed to demonstrate the clinical characteristics of patients affected by COVID-19, in our tertiary teaching hospital. Medical records and compiled data of 668 patients with suspected COVID-19 were obtained retrospectively between January to April 2020. The present study outcomes included demographic features of infected patients, underlying diseases and conditions, the relationship between the results of reverse transcription-polymerase chain reaction (RT-PCR) or CT-scan with the manifestations of the disease, mortality rate, and age distribution of fatalities among men and women. The median age of hospitalized patients was 63 years old (from 18 to 94). The patients' chief complaints in the admission time were cough, dyspnea, fever, and gastrointestinal problems, respectively. Hospitalized patients' common comorbidities were hypertension (HTN), and cardiovascular disease (CVD) (24%), diabetes mellitus (DM) (21.5%), asthma, or chronic obstructive pulmonary disease (COPD) (6%), or other underlying diseases (15.5%). One-third of patients had no comorbidity according to the data of medical records. In hospitalized patients, 169 (84.5%) had positive RT-PCR, and 156 (78%) had positive chest CT findings. The mortality rate of males was higher than females (66.3% vs. 33.3%) and in patients with positive RT-PCR compared to patients with positive chest CT-scan findings. The majority of deaths had a history of DM or HTN/CVD in their medical records. The chief complaint of patients was cough. DM and HTN or CVD were the common underlying disease related to death in hospitalized cases. Besides, the hospitalization and mortality rate in males was higher than in females. About 87% of dead hospitalized cases had positive RT-PCR results, and this rate was 82% for chest CT results.


Assuntos
Asma , COVID-19 , Diabetes Mellitus , Hipertensão , Pandemias , Doença Pulmonar Obstrutiva Crônica , SARS-CoV-2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/mortalidade , Asma/patologia , Asma/terapia , COVID-19/mortalidade , COVID-19/patologia , COVID-19/terapia , Comorbidade , Diabetes Mellitus/mortalidade , Diabetes Mellitus/patologia , Diabetes Mellitus/terapia , Feminino , Humanos , Hipertensão/mortalidade , Hipertensão/patologia , Hipertensão/terapia , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/terapia
19.
J Med Chem ; 64(9): 5323-5344, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33872507

RESUMO

Herein we describe the discovery, mode of action, and preclinical characterization of the soluble guanylate cyclase (sGC) activator runcaciguat. The sGC enzyme, via the formation of cyclic guanosine monophoshphate, is a key regulator of body and tissue homeostasis. sGC activators with their unique mode of action are activating the oxidized and heme-free and therefore NO-unresponsive form of sGC, which is formed under oxidative stress. The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. We overcame limitations of first-generation sGC activators and identified a new chemical class via high-throughput screening. The investigation of the structure-activity relationship allowed to improve potency and multiple solubility, permeability, metabolism, and drug-drug interactions parameters. This program resulted in the discovery of the oral sGC activator runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy.


Assuntos
Desenho de Fármacos , Ativadores de Enzimas/química , Guanilil Ciclase Solúvel/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Cães , Ativadores de Enzimas/metabolismo , Ativadores de Enzimas/farmacologia , Ativadores de Enzimas/uso terapêutico , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Simulação de Dinâmica Molecular , Ratos , Ratos Endogâmicos SHR , Solubilidade , Guanilil Ciclase Solúvel/metabolismo , Relação Estrutura-Atividade
20.
Life Sci ; 278: 119540, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33930369

RESUMO

AIM: The aim of our study was to clarify the cardioprotection of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in spontaneously hypertensive rats (SHR). MAIN METHODS: Adult male rats were divided into normal blood pressure Wistar-Kyoto rats (WKY) control (WKY-CON), WKY rats with CIHH treatment (WKY-CIHH), SHR control (SHR-CON) and SHR with CIHH treatment (SHR-CIHH) groups. SHR-CIHH and WKY-CIHH rats were subjected to hypobaric hypoxia simulating 4000-m altitude for 35 days, 5 h per day. Arterial blood pressure and cardiac function parameters, including ejection fraction, fractional shortening and left ventricular (LV) wall thickness, were evaluated. Cardiac pathomorphology and myocardial fibrosis were determined. The expression of angiotensin-converting enzyme (ACE), ACE2, Ang II, Ang1-7, AT1 receptor, Mas receptor, IL-6, TNF-α,IL-10, SOD and MDA were assayed in myocardium. KEY FINDINGS: CIHH significantly decreased arterial blood pressure, alleviated LV hypertrophy, and improved cardiovascular function in SHR (P < 0.05-0.01). Also, CIHH protected SHR heart against morphological changes and fibrosis. In addition, CIHH significantly down-regulated the ACE/Ang II/AT1 receptor axis and up-regulated the ACE2/Ang1-7/Mas axis of renin-angiotensin system (RAS) in SHR (P < 0.05-0.01). CIHH significantly reduced IL-6, TNF-α, and MDA levels, but increased IL-10 and SOD in SHR myocardium (P < 0.05-0.01). SIGNIFICANCE: The CIHH treatment protected the heart of SHR against LV remodelling and myocardial fibrosis, which might be carried out through a balance in the ACE/Ang II/AT1 axis and the ACE2/Ang1-7/Mas axis of the RAS to reduce inflammation, and inhibit oxidative stress.


Assuntos
Doença da Altitude/epidemiologia , Hipertensão/epidemiologia , Hipertensão/patologia , Miocárdio/patologia , Sistema Renina-Angiotensina , Remodelação Ventricular , Altitude , Animais , Fibrose , Hipertensão/metabolismo , Masculino , Miocárdio/metabolismo , Oxigênio/metabolismo , Fatores de Proteção , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
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