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1.
BMC Res Notes ; 14(1): 244, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193266

RESUMO

OBJECTIVE: Glutathione S-transferases have been associated with experimental resistance to some drugs. The present study investigated the factors associated with blood pressure control in patients with essential hypertension, especially the role of GSTT1 and GSTM1 genes polymorphisms. This cross-sectional study in Burkina Faso consisted of 200 patients with essential hypertension and under treatment. RESULTS: In the present study, 57.5% (115/200) of patients had their hypertension under control. No statistically significant difference was found between controlled and uncontrolled groups for anthropometric and biochemical parameters as well as for GSTT1 or GSTM1 gene polymorphisms (all p > 0.05). Current alcohol consumption (OR = 3.04; CI 1.88-6.13; p < 0.001), Physical inactivity (OR = 3.07; CI 1.71-5.49; p < 0.001), severe hypertension before any treatment (Grade III [OR = 3.79; CI 2.00-7.17; p < 0.001]) and heart damage (OR = 3, 14; CI 1.59-6.02; p < 0.001) were statistically more frequent in uncontrolled essential hypertensive patients than controlled hypertensive patients.


Assuntos
Predisposição Genética para Doença , Hipertensão , Pressão Sanguínea , Burkina Faso , Estudos de Casos e Controles , Estudos Transversais , Genótipo , Glutationa Transferase/genética , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Polimorfismo Genético
2.
Curr Hypertens Rep ; 23(5): 28, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33961141

RESUMO

PURPOSE OF REVIEW: To review the current knowledge on interactions between dietary factors and microRNAs (miRNAs) in essential hypertension (EH) pathogenesis. RECENT FINDINGS: There exists an integration of maintenance signals generated by genetic, epigenetic, immune, and environmental (e.g., dietary) factors that work to sustain balance in the gut-liver axis. It is well established that an imbalance in this complex, intertwined system substantially increases the risk for EH. As such, pertinent research has been taken to decipher how each signal operates in isolation and together in EH progression. Recent literature indicates that both macro- and micronutrients interrupt regulatory miRNA expressions and thus, alter multiple cellular processes that contribute to EH and its comorbidities. We highlight how carbohydrates, lipids, proteins, salt, and potassium modify miRNA signatures during EH. The disruption in miRNA expression can negatively impact communication systems such as over activating the renin-angiotensin-aldosterone system, modulating the vascular smooth muscle cell phenotype, and promoting angiogenesis to favor EH. We also delineate the prognostic value of miRNAs in EH and discuss the pros and cons of surgical vs dietary prophylactic approaches in EH prevention. We propose that dietary-dependent perturbation of the miRNA profile is one mechanism within the gut-liver axis that dictates EH development.


Assuntos
Hipertensão , MicroRNAs , Epigênese Genética , Hipertensão Essencial , Humanos , Hipertensão/genética , Fígado/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Sistema Renina-Angiotensina
3.
BMC Res Notes ; 14(1): 186, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001234

RESUMO

OBJECTIVE: African ancestry seems to be a risk factor for hypertension; however, few genetic studies have addressed this issue. This study aimed to investigate the prevalence of polymorphisms NOS3; rs1799983, IGFBP3; rs11977526 and TCF7L2; rs7903146 in Brazilian women of African descent and their association with hypertension. RESULTS: The prevalences of the less frequent genotypes were 26.5% TT genotype of NOS3; rs1799983, 16.7% AA genotype of IGFBP3; rs11977526, and 18.3% TT genotype of TCF7L2; rs7903146. For these conditions, the prevalence of hypertension and PR (adjusted) relatively to the ancestral genotype were, respectively: 52.0% vs 24.5% (PR = 1.54; p < 0.001), 62.0% vs 24.1% (PR = 1.59; p < 0.001), and 38.9% vs 27.9% (PR = 0.86; p = 0.166). Associations with hypertension were statistically significant, except for the TCF7L2; rs7903146 polymorphism, after adjusted analysis. Brazilian Afro-descendant women with the TT genotype for the NOS3 gene and the AA genotype for the IGFBP3 gene are more susceptible to hypertension. The understanding of underlying mechanisms involving the pathogenesis of hypertension can motivate research for the development of new therapeutic targets related to nitric oxide metabolism and the management of oxidative stress.


Assuntos
Hipertensão , Polimorfismo de Nucleotídeo Único , Brasil/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Óxido Nítrico Sintase Tipo III/genética , Prevalência , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
4.
Nat Genet ; 53(5): 630-637, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33958779

RESUMO

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.


Assuntos
Predisposição Genética para Doença , Genômica , Hipertensão/genética , Rim/patologia , Processamento Alternativo/genética , Pressão Sanguínea/genética , Metilação de DNA/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
5.
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
6.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925539

RESUMO

Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene CYP11B2 is regulated by angiotensin II and potassium. DNA methylation negatively regulates AGT and CYP11B2 expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the CYP11B2 promoter region, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac AGT expression. CpG dinucleotides in the CYP11B2 promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated CYP11B2 promoter. Low salt intake and angiotensin II infusion lead to upregulation of CYP11B2 expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases CYP11B2 expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased CYP11B2 expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both AGT and CYP11B2 contribute to the pathogenesis of cardiovascular diseases.


Assuntos
Angiotensinogênio/genética , Doenças Cardiovasculares/genética , Citocromo P-450 CYP11B2/genética , Aldosterona , Angiotensina II , Angiotensinogênio/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Citocromo P-450 CYP11B2/metabolismo , Metilação de DNA/genética , Epigênese Genética/efeitos dos fármacos , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Hipertensão/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Fatores de Transcrição/metabolismo
7.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921209

RESUMO

Gastrin, secreted by G-cells, and glucagon-like peptide-1 (GLP-1), secreted by L-cells, may participate in the regulation of sodium balance. We studied the effect of sodium in mice in vivo and mouse ileum and human L-cells, on GLP-1 secretion, and the role of NFAT5 and gastrin-releasing peptide receptor (GRPR) in this process. A high-sodium diet increases serum GLP-1 levels in mice. Increasing sodium concentration stimulates GLP-1 secretion from mouse ileum and L-cells. GRP enhances the high sodium-induced increase in GLP-1 secretion. High sodium increases cellular GLP-1 expression, while low and high sodium concentrations increase NFAT5 and GRPR expression. Silencing NFAT5 in L-cells abrogates the stimulatory effect of GRP on the high sodium-induced GLP-1 secretion and protein expression, and the sodium-induced increase in GRPR expression. GLP-1 and gastrin decrease the expression of Na+-K+/ATPase and increase the phosphorylation of sodium/hydrogen exchanger type 3 (NHE3) in human renal proximal tubule cells (hRPTCs). This study gives a new perspective on the mechanisms of GLP-1 secretion, especially that engendered by ingested sodium, and the ability of GLP-1, with gastrin, to decrease Na+-K+/ATPase expression and NHE3 function in hRPTCs. These results may contribute to the better utilization of current and future GLP-1-based drugs in the treatment of hypertension.


Assuntos
Gastrinas/genética , Peptídeo 1 Semelhante ao Glucagon/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Hipertensão/genética , Fatores de Transcrição/genética , Animais , Células Secretoras de Gastrina/metabolismo , Regulação da Expressão Gênica/genética , Inativação Gênica , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Túbulos Renais Proximais/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Sódio/metabolismo , Sódio/farmacologia , Trocador 3 de Sódio-Hidrogênio/genética , ATPase Trocadora de Sódio-Potássio/genética
8.
Med Sci Monit ; 27: e930552, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33911065

RESUMO

BACKGROUND Hypertension-related microRNA(miR)-1283 and its target gene, activating transcription factor-4 (ATF4), can regulate vascular endothelial dysfunction. This study aimed to explore whether miR-1283 prevents hypertension through targeting ATF4. MATERIAL AND METHODS Transcriptome sequencing was performed after overexpression or inhibition of miR-1283 in human amniotic epithelial cells (HAECs). After miR-1283 was overexpressed or inhibited in HAECs, ATF4+/- and wild-type mice were induced with a high-salt diet. We detected the expression of ATF4, C/EBP-homologous protein (CHOP), BH3-interacting domain death agonist (BID), Bcl-2, Bcl-2-like protein 11 (BIM), Bcl-2-like protein 1 (BCL-X), and caspase-3 by PCR and western blotting. We detected the changes of vasoactive substances including nitric oxide (NO), endothelin 1 (ET-1), endothelial protein C receptor (EPCR), thrombin (TM), and von Willebrand factor (vWF) by ELISA. RESULTS Compared with that of the miR-1283- inhibited group, NO was higher in the miR-1283 overexpression group, while the expression of ET-1, EPCR, TM, and vWF were lower. Similarly, compared with that of the miR-1283 inhibited group, the expression of ATF4, CHOP, BID, BIM, and caspase-3 in the miR-1283 overexpression group was downregulated, while the expression of BCL-2 and BCL-X was upregulated (P<0.05). In vivo experiments showed the lack of ATF4 gene could prevent hypertension in mice induced by high-salt diet and protect endothelial function. CONCLUSIONS The mechanism of regulating blood pressure and endothelial function of the miR-1283/ATF4 axis was related to inhibiting endoplasmic reticulum stress and cell apoptosis through the ATF4/CHOP signaling pathway. Therefore, the miR-1283/ATF4 axis may be a target for the prevention and treatment of hypertension.


Assuntos
Fator 4 Ativador da Transcrição/genética , Estresse do Retículo Endoplasmático/genética , Hipertensão/genética , MicroRNAs/genética , Transdução de Sinais/genética , Fator de Transcrição CHOP/genética , Animais , Apoptose/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Proteína 11 Semelhante a Bcl-2/genética , Células Cultivadas , Regulação para Baixo/genética , Células Epiteliais/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-2/genética , Regulação para Cima/genética , Proteína bcl-X/genética
9.
Nat Commun ; 12(1): 2337, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879782

RESUMO

While recent advancements in computation and modelling have improved the analysis of complex traits, our understanding of the genetic basis of the time at symptom onset remains limited. Here, we develop a Bayesian approach (BayesW) that provides probabilistic inference of the genetic architecture of age-at-onset phenotypes in a sampling scheme that facilitates biobank-scale time-to-event analyses. We show in extensive simulation work the benefits BayesW provides in terms of number of discoveries, model performance and genomic prediction. In the UK Biobank, we find many thousands of common genomic regions underlying the age-at-onset of high blood pressure (HBP), cardiac disease (CAD), and type-2 diabetes (T2D), and for the genetic basis of onset reflecting the underlying genetic liability to disease. Age-at-menopause and age-at-menarche are also highly polygenic, but with higher variance contributed by low frequency variants. Genomic prediction into the Estonian Biobank data shows that BayesW gives higher prediction accuracy than other approaches.


Assuntos
Idade de Início , Genoma Humano , Modelos Genéticos , Herança Multifatorial , Fatores Etários , Algoritmos , Teorema de Bayes , Doenças Cardiovasculares/genética , Simulação por Computador , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/genética , Estônia , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Hipertensão/genética , Menarca/genética , Menopausa/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Reino Unido
10.
Nutrients ; 13(3)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800142

RESUMO

Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms.


Assuntos
Aldosterona/biossíntese , Hiperaldosteronismo/genética , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertensão/genética , Canais Iônicos/genética , Mutação
11.
Zhen Ci Yan Jiu ; 46(3): 187-93, 2021 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-33798290

RESUMO

OBJECTIVE: To investigate the effect of electroacupuncture (EA) at "Taichong"(LR3) on blood pressure, sympathetic nerve activity, baroreflex sensitivity, and α 2-adrenergic receptor (α2AR) expression in nucleus tractus solitarii (NTS) in hypertensive rats, so as to reveal its mechanisms underlying improvement of hypertension. METHODS: Male Sprague Dawley rats were randomly divided into 4 groups: sham-operation, model, EA, and sham-EA (non-acupoint) groups, with 12 rats in each group. The hypertension model was established by occlusion of the right renal aorta (two-kidney-one clip method). Rats of the sham-operation group received the same surgery but without occlusion of the renal artery. EA (2 Hz/15 Hz, 2 mA) was applied to bilateral LR3 for 30 min, once a day for 28 days, and sham EA was applied to the skin of the rat tail near the buttock on both sides. The mean arterial pressure (MAP) of the abdominal aorta and heart rate (HR) were recorded. The autonomic nerve function was assessed by using frequency domain analysis of heart rate variability (HRV), and the baroreflex sensitivity detected by sequential method. Plasma norepinephrine (NE) level was measured by ELISA, and the α2AR positive neurons and α2AR protein expression in NTS were detected by using fluorescence immunohistochemistry and Western blot, respectively. The functions of α2AR within the NTS in modulating MBP and HR were verified by microinjection of its agonist (clonidine) and antagonist (yohimbine) separately. RESULTS: Compared to the sham operation rats, the hypertension rats displayed significant increases in the MAP (P<0.01), plasma norepinephrine content (P<0.01), ratios of low frequency/total power (LF/TP) and low frequency/high frequency (LF/HF) (P<0.01), and significant reduction in the overall gain, uplink sequence gain and downlink sequence gain of baroreflex (P<0.01), the number α2AR positive neurons and α2AR protein expression level in NTS (P<0.01). The rats in the EA group (rather than in the sham-EA group) showed significant reduction in MAP at the 3rd and 4th week, plasma NE content, LF/TP and LF/HF (P<0.01), and obvious increase in the overall gain, uplink sequence gain and downlink sequence gain of baroreflex (P<0.01), and the number of α2AR positive neurons and α2AR protein expression in comparison (P<0.05) with those of the model group. Microinjection of clonidine into NTS induced an evident decrease in both MAP and HR in the model group relevant to the sham operation group (P<0.01), while the MAP and HR changes of the EA (not sham EA) group were considerably bigger than those of the model group (P<0.05), being similar to those of the sham-operation group (P>0.05), which suggested an elimination of the BP-lowering effect of clonidine after EA. CONCLUSION: EA at LR3 can reduce MBP, sympathetic activities, improve baroreflex sensitivity in renovascular hypertensive rats, which may be associated with its effects in up-regulating the decreased NTS α2AR expression and functional activities.


Assuntos
Eletroacupuntura , Hipertensão , Animais , Barorreflexo , Hipertensão/genética , Hipertensão/terapia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos , Núcleo Solitário
12.
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
13.
Medicine (Baltimore) ; 100(15): e25530, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847678

RESUMO

OBJECTIVE: The present study aimed to conduct a systematic review and meta-analysis to evaluate the relationships between ATP2B1 gene polymorphisms with blood pressure (BP) level and susceptibility to hypertension. METHODS: PubMed, Web of Science, Embase and China National Knowledge Infrastructure (CNKI) Databases were systematically searched by 2 independent researchers to screen studies on ATP2B1 gene polymorphisms and BP related phenotypes. The records retrieval period was limited from the formation of the database to March 4, 2021. Pooled odds rations (ORs) or ß and their 95% confidence intervals (95%CI) were calculated to assess the association between ATP2B1 gene polymorphisms and the risk of hypertension or BP levels. Publication bias and sensitivity analysis were conducted to find potential bias. All the statistical analysis were conducted with Stata version 11.0 software. RESULTS: A total of 15 articles were ultimately included in the present study, including 15 polymorphisms of ATP2B1 gene. Nine articles (N = 65,362) reported the polymorphism rs17249754, and 7 articles(N = 91,997) reported rs2681472 (both loci were reported in 1 article). Meta-analysis showed that rs17249754 (G/A) and rs2681472 (A/G) were associated with the susceptibility to hypertension (rs17249754: OR = 1.19, 95%CI: 1.10-1.28; rs2681472: OR = 1.15, 95%CI: 1.12-1.17), and were positively associated with systolic BP (SBP) and diastolic blood pressure (DBP) (rs17249754: SBP, ß=1.01, 95%CI: 0.86-1.16, DBP, ß=0.48, 95%CI: 0.30-0.66; rs2681472: SBP, ß=0.92, 95%CI: 0.77-1.07, DBP, ß=0.50, 95%CI: 0.42-0.58) in the additive genetic model. Subgroup analysis stratified by race, population, sample size, and BP measurement method revealed that the association between A allele in rs2681472 polymorphism and risk of hypertension was slightly stronger in European (EUR) populations (OR = 1.16, 95%CI: 1.13-1.20) than in East Asians (OR = 1.14, 95%CI: 1.10-1.17). While in East Asians, relation between rs17249754 with risk of hypertension (OR = 1.19, 95%CI: 1.10-1.28) is stronger than rs2681472 (OR = 1.14, 95%CI: 1.10-1.17). CONCLUSIONS: Our study demonstrated that ATP2B1 gene polymorphism rs2681472 and rs17249754 were associated with BP levels and the susceptibility to hypertension.


Assuntos
Pressão Sanguínea/genética , Predisposição Genética para Doença/genética , Hipertensão/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo Genético/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo
14.
Int J Clin Pharmacol Ther ; 59(7): 506-510, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33769277

RESUMO

OBJECTIVE: To identify single nucleotide variants (SNVs) associated with lisinopril effectiveness. MATERIALS AND METHODS: This was an observational study using a candidate gene approach to examine SNVs associated with lisinopril effectiveness. Drug effectiveness was defined as 10% decrease in systolic blood pressure at 1 week follow-up. We used the Illumina GWAS MEGA chip to examine variants in the renin/angiotensin pathway that may be associated with drug effectiveness. RESULTS: 61 subjects were enrolled, and 33 (54.1%) were responsive to lisinopril therapy. SNVs in AGT (p = 0.0141), REN (p = 0.0192), and ACE2 (p = 0.0002) were found to be associated with successful treatment on lisinopril. Conclusion and relevance: SNVs in the renin and angiotensin pathway are associated with lisinopril effectiveness in a pilot cohort of patients with uncontrolled hypertension.


Assuntos
Hipertensão , Lisinopril , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Genômica , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Projetos Piloto , Sistema Renina-Angiotensina
15.
Biochem Pharmacol ; 186: 114489, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33647262

RESUMO

RATIONALE: Hypertension in obesity has become a major threat for public health. Omentin-1, a novel adipokine, is down-regulated in obesity. Tetrahydroxystilbene glycoside (TSG) is the main ingredient extracted from Polygonum multiflorum Thunb (PMT), a traditional Chinese medicinal herb safely used for protecting cardiovascular systems over bimillennium. This study aims to examine (i) the impact of omentin-1 downregulation on obesity-related hypertension in murine models and the underlying mechanisms; (ii) whether tetrahydroxystilbene glycoside (TSG) improved endothelial dysfunction and obesity-associated hypertension via the increase of omentin-1. METHODS: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and omentin-1 knockout (OMT-/-) mice were used. In vitro, human umbilical vein endothelial cells (HUVECs) and mature adipocytes differentiated from human visceral preadipocyte (HPA-v) were maintained in a co-culture system. RESULTS: TSG was the main active component of PMT reducing systolic blood pressure and improving endothelial vasodilation. Fortnight-TSG treatment (100 mg/kg/day) increased serum omentin-1 level, also activated Akt/eNOS signaling and enhanced NO bioactivity; decreased expression of NOX2 and p22phox, suppressed production of superoxide and peroxynitrite anion. OMT-/- mice showed elevated blood pressure and impaired endothelial vasorelaxation, whereas hypotensive effect of TSG was blunted. In co-culture system, TSG incubation promoted binding of peroxisome proliferator-activated receptor-γ (PPAR-γ) and Itln-1 promoter in adipocytes, activated Akt/eNOS/NO signaling and attenuated oxidative/nitrative stress in HUVECs. Suppression of Itln-1 with siRNA significantly blocked the protective effect of TSG in vitro. CONCLUSIONS: Down-regulation of omentin-1 induces endothelial dysfunction and hypertension in obesity. TSG treatment (at least partially) increases omentin-1 via promoting binding of PPAR-γ and Itln-1 promoter in adipose tissues, subsequently exerts protective effects on endothelial function via activating Akt/eNOS/NO signaling and attenuating oxidative/nitrative stress. These results suggest that TSG could be developed as a promising anti-hypertension agent that protects against endothelial dysfunction and obesity-associated cardiovascular diseases.


Assuntos
Citocinas/biossíntese , Citocinas/deficiência , Endotélio Vascular/efeitos dos fármacos , Proteínas Ligadas por GPI/biossíntese , Proteínas Ligadas por GPI/deficiência , Glucosídeos/uso terapêutico , Hipertensão/tratamento farmacológico , Lectinas/biossíntese , Lectinas/deficiência , Estilbenos/uso terapêutico , Animais , Citocinas/genética , Endotélio Vascular/metabolismo , Proteínas Ligadas por GPI/genética , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Lectinas/genética , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Zucker , Estilbenos/metabolismo , Estilbenos/farmacologia
16.
Acta Diabetol ; 58(7): 911-917, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33721078

RESUMO

BACKGROUND: Individuals with type 1 diabetes have a markedly increased risk of stroke. In the general population, genetic predisposition has been linked to increased risk of stroke, but this has not been assessed in type 1 diabetes. Our aim was, therefore, to study how parental risk factors affect the risk of stroke in individuals with type 1 diabetes. METHODS: This study represents an observational follow-up of 4011 individuals from the Finnish Diabetic Nephropathy Study, mean age at baseline 37.6 ± 11.9 years. All strokes during follow-up were verified from medical records or death certificates. The strokes were classified as either ischemic or hemorrhagic. All individuals filled out questionnaires concerning their parents' medical history of hypertension, diabetes, stroke, and/or myocardial infarction. RESULTS: During a median follow-up of 12.4 (10.9-14.2) years, 188 individuals (4.6%) were diagnosed with their first ever stroke; 134 were ischemic and 54 hemorrhagic. In Cox regression analysis, a history of maternal stroke increased the risk of hemorrhagic stroke, hazard ratio 2.86 (95% confidence interval 1.27-6.44, p = 0.011) after adjustment for sex, age, BMI, retinal photocoagulation, and diabetic kidney disease. There was, however, no association between maternal stroke and ischemic stroke. No other associations between parental risk factors and ischemic or hemorrhagic stroke were observed. CONCLUSION: A history of maternal stroke increases the risk of hemorrhagic stroke in individuals with type 1 diabetes. Other parental risk factors seem to have limited impact on the risk of stroke.


Assuntos
Diabetes Mellitus Tipo 1 , Fatores de Risco de Doenças Cardíacas , Pais , Acidente Vascular Cerebral/etiologia , Adulto , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/genética , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Feminino , Finlândia/epidemiologia , Seguimentos , Predisposição Genética para Doença/epidemiologia , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética
17.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760199

RESUMO

Pregnancy­induced hypertension is often accompanied by preeclampsia. The present study investigated whether microRNA (miR)­27b­3p affected the occurrence of preeclampsia by regulating the function of endothelial cells. Expressions levels of miR­27b­3p and ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) were determined using reverse­transcription quantitative PCR. miR­27b­3p targeting ATP2B1 was predicted using bioinformatics and further confirmed by dual­luciferase reporter assays. Cell Counting Kit­8, Transwell and Matrigel tube formation assays were performed to detect the effects of miR­27b­3p on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), respectively. Moreover, HTR8/SVneos cells were co­cultured with HUVECs to detect the invasion of trophoblast cells, and the expression levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)­2 and MMP­9 of HUVECs and HTR8/SVneos were detected by western blotting. Expression levels of miR­27b­3p were upregulated in the serum of patients with hypertension and preeclampsia, which could target and regulate the expression of ATP2B1. The expression levels of miR­27b­3p were increased and those of ATP2B1 were reduced in HUVECs from hypertensive serums. Moreover, miR­27b­3p mimics reduced the expression level of ATP2B1, and miR­27b­3p inhibitor reversed the effect of hypertensive serum on ATP2B1 expression. Furthermore, patients with hypertension showed increased endothelial dysfunction, reduced trophoblastic invasion and the expressions of VEGF, MMP­2 and MMP­9, and miR­27b­3p mimics and silencing of ATP2B1 produced similar results to HUVECs. The miR­27b­3p inhibitor reversed the effect of hypertensive serum, and silencing of ATP2B1 inhibited the improvement of miR­27b­3p inhibitor to HUVECs and HTR­8/SVneo cells in proliferation, migration and tube formation. The current findings suggested that miR­27b­3p promoted proliferation, migration and tube formation of HUVECs and enhanced invasion of trophoblast cells, via regulation of ATP2B1. Thus, miR­27b­3p could be considered as a molecular risk factor in the pathogenesis and development of preeclampsia.


Assuntos
Hipertensão Induzida pela Gravidez/genética , Hipertensão/genética , MicroRNAs/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Pré-Eclâmpsia/genética , Adenosina Trifosfatases/sangue , Adulto , Proliferação de Células/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/sangue , Hipertensão/patologia , Hipertensão Induzida pela Gravidez/sangue , Hipertensão Induzida pela Gravidez/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/patologia , Gravidez , Trofoblastos/metabolismo , Trofoblastos/patologia
18.
Ter Arkh ; 93(1): 41-43, 2021 Jan 10.
Artigo em Russo | MEDLINE | ID: mdl-33720624

RESUMO

AIM: To study the significance of the rs1378942 polymorphisms of the CSK gene and rs2200733 (chromosome 4q25) in the progression of AF in men with AH and AO. MATERIALS AND METHODS: In an observational cohort study, 116 men aged 4565 years were followed. Of these, 57 patients with AF, AH and AO and a control group including 59 patients with AF, AH and without AO. Testing of polymorphism rs1378942 of the CSK gene and rs2200733 of chromosome 4q25 using polymerase chain reaction with restriction fragment length polymorphism. All statistical calculations were performed using the Rstudio program (version 0.99.879 20092016 RStudio, Inc., USA). RESULTS: The average age of all studied patients was 53.37.1 years. When dividing patients with AF and AH into groups based on the presence/absence of AO, it turned out that in the subgroups of carriers of different genotypes of the rs1378942 polymorphism of the CSK gene there are significant differences in BMI: in the group with BMI, there is an increase in the indicator in the series of CC, AC, AA genotypes. The highest BMI value in carriers of the CC genotype (p0.03) was in the group with AO. In the subgroups of carriers of different rs2200733 genotypes of chromosome 4q25, CC has the highest BMI (p0.05). It was proved that in the group with AO, the progression of AF occurred 2.57 times more often than in the group without AO (p0.003). CONCLUSION: In men with AF and AH, single nucleotide polymorphisms rs1378942 of the CSK gene and rs2200733 of chromosome 4q25 are associated with BMI. The heterozygous genotype AC rs1378942 in the CSK gene is significantly more common in patients, regardless of the presence of AO. In the group with AO, the progression of AF occurred 2.57 times more often than in the group without AO.


Assuntos
Fibrilação Atrial , Hipertensão , Obesidade Abdominal , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/genética , Predisposição Genética para Doença , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/epidemiologia , Obesidade Abdominal/genética , Polimorfismo de Nucleotídeo Único
19.
Zhongguo Zhong Yao Za Zhi ; 46(1): 6-14, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33645045

RESUMO

Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure, which may be accompanied by functional or organic damage of heart, brain, kidney and other organs. The pathogenesis and development of hypertension are affected by genetic, environmental, epigenetic, intestinal microbiota and other factors. They are the result of multiple factors that promote the change of blood pressure level and vascular resistance. G protein coupled receptors(GPCRs) are the largest and most diverse superfamily of transmembrane receptors that transmit signals across cell membranes and mediate a large number of cellular responses required by human physiology. A variety of GPCRs are involved in the control of blood pressure and the maintenance of normal function of cardiovascular system. Hypertension contributes to the damages of heart, brain, kidney, intestine and other organs. Many GPCRs are expressed in various organs to regulate blood pressure. Although many GPCRs have been used as therapeutic targets for hypertension, their efficacy has not been fully studied. The purpose of this paper is to elucidate the role of GPCRs in blood pressure regulation and its distribution in target organs. The relationship between GPCRs related to intestinal microorganisms and blood pressure is emphasized. It is proposed that traditional Chinese medicine may be a new way to treat hypertension by regulating the related GPCRs via intestinal microbial metabolites.


Assuntos
Microbioma Gastrointestinal , Hipertensão , Pressão Sanguínea , Proteínas de Ligação ao GTP , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
20.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669059

RESUMO

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.


Assuntos
Hipertensão/metabolismo , Nefropatias/metabolismo , Rim/crescimento & desenvolvimento , Néfrons/crescimento & desenvolvimento , Sistema Renina-Angiotensina , Renina/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Disbiose/metabolismo , Epigênese Genética , Humanos , Hipertensão/genética , Rim/metabolismo , Nefropatias/enzimologia , Nefropatias/genética , Néfrons/citologia , Néfrons/metabolismo , Óxido Nítrico/deficiência , Óxido Nítrico/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia
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