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1.
Anticancer Res ; 39(8): 4503-4509, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366552

RESUMO

BACKGROUND/AIM: Oral administration of Pantoea agglomerans-derived lipopolysaccharide (LPSp) has been reported to have a preventive effect against various lifestyle-related diseases. Therefore, we examined the preventive effect on high blood pressure, which is a kind of reserve arm for lifestyle-related diseases. MATERIALS AND METHODS: Spontaneous hypertensive rat (SHR) and WKY rat were bred from 6 to 16 weeks of age. SHR were orally administered 100 µg/kg LPSp and 0.1% NaCl, and blood pressure was measured at 6, 10, 13 and 16 weeks. Furthermore, at 16 weeks of age, blood biochemical markers were measured and microbial community composition was analyzed. RESULTS: SHRs developed hypertension with age, which was exacerbated by salt loading. Although there was almost no reduction in blood pressure in SHRs that received LPSp. It was suppressed at 13-16 weeks of age in those with salt loading. CONCLUSION: Oral administration of LPSp showed a preventive effect on salt-loaded hypertension.


Assuntos
Citocinas/genética , Hipertensão/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Pantoea/química , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hipertensão/genética , Hipertensão/patologia , Lipopolissacarídeos/química , Masculino , Fagocitose/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Sais/toxicidade
2.
Ter Arkh ; 91(1): 71-77, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-31090375

RESUMO

AIM: To evaluate the association of a complex of cardiovascular risk factors and genetic markers with the development of high albuminuria among patients with arterial hypertension in the population of Mountain Shoriya, taking into account ethnicity. MATERIALS AND METHODS: A clinical epidemiological study of a compactly residing population in remote areas of Mountain Shoria was carried out. 1409 people were examined [901 people - representatives of the indigenous nationality (Shorians), 508 people - representatives of non-indigenous nationality (90% of them are Caucasians)]. Hypertension was diagnosed according to the National Guidelines of the Russian Society of Cardiology/the Russian Medical Society on Arterial Hypertension (2010). All patients underwent clinical, laboratory and instrumental investigation. To study the state of the kidneys, the concentration (the presence of elevated levels) of albumin (albuminuria) in the morning portion of urine by an immunoturbidimetric method was analyzed. Polymorphisms of genes ACE (I/D, rs4340), АGT (c.803T>C, rs699), AGTR1 (А1166С, rs5186), ADRB1 (с.145A>G, Ser49Gly, rs1801252), ADRA2B (I/D, rs28365031), MTHFR (c.677С>Т, Ala222Val, rs1801133) and NOS3 (VNTR, 4b/4a) were tested using PCR. RESULTS: In the group of shors with arterial hypertension, high albuminuria was associated with polymorphisms of the ACE genes (OR=2.05), ADRA2B (OR=6.00), elevated triglyceride level (OR=2.86), decreased index of cholesterol of high density lipoproteins (OR=5.57) and increased index of low density lipoproteins (OR=2.49); in the new population - with polymorphisms of the AGTR1 genes (OR=8.66), ADRA2B (OR=6.53), MTHFR (OR=7.16), obesity (OR=2.72), and abdominal obesity (OR=3.14). CONCLUSION: The primary predictors determining the development of high albuminuria among patients with arterial hypertension in both ethnic groups were genetic ones. In addition to them, non-genetic risk factors also contributed to the development of this organ damage to the kidneys: age and lipid metabolism disorders in representatives of indigenous nationality; age and abdominal obesity in the examined patients non-indigenous nationality.


Assuntos
Albuminas/metabolismo , Albuminúria/etnologia , Doenças Cardiovasculares/genética , Grupos Étnicos/genética , Hipertensão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genética , Receptores Adrenérgicos alfa 2/genética , Albuminúria/genética , Doenças Cardiovasculares/etnologia , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hipertensão/etnologia , Lipoproteínas HDL/metabolismo , Obesidade Abdominal/etnologia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Fatores de Risco , Federação Russa/epidemiologia , Triglicerídeos/metabolismo
3.
Wiad Lek ; 72(4): 568-574, 2019.
Artigo em Ucraniano | MEDLINE | ID: mdl-31055534

RESUMO

OBJECTIVE: Introduction: Arterial hypertension is a multifactorial disease developing under the influence of environmental factors and is genetically determined. One of the genetic markers that is of primary importance in the disease development is endothelin-1 gene (EDN1). Today the association between the polymorphic variants of this gene, particularly Lys198Asn-polymorphism, and the development of arterial hypertension in different populations of the world has been proved. The aim: To study the association between the Lys198Asn-polymorphism of the endothelin-1 gene and the development of arterial hypertension in Ukrainian population. PATIENTS AND METHODS: Materials and methods: The genotypes were determined by the polymerase chain reaction method, followed by the analysis of the restriction fragment length (PCR-RFLP) in venousblood of 160 patients with arterial hypertension and 110 people in the control group. The statistical analysis was performed using SPSS-17.0. RESULTS: Results: As a result of genotyping, it was found that in the group of patients with arterial hypertension the ratio of homozygote of the major allele (Lys/Lys), heterozygote (Lys/Asn) and homozygote of the minor allele (Asn/Asn) was 74 (46.3%), 73 ( 45.6%), 13 (8.1%), while in control - 66 (60.0%), 41 (37.3%), 3 (2.7%) respectively. The distribution of genotypes in the experimental groups was statistically significant (χ2 = 6.66; P = 0.036). By the method of binary logistic regression within the dominant and additive model of inheritance, a reliable association between the genotype of the Lys198Asn-polymorphism of the ET-1 gene and the development of arterial hypertension was established. It was shown that carriers of minor allele (Lys/Asn+Asn/Asn) have a risk of arterial hypertension 1.7 (95 % CI = 1.066 - 2.851), and homozygotes Asn/Asn 3.9 (95 % CI = 1.016 - 9.566) times higher than people with Lys/Lys genotype. In addition, smoking patients with Lys/Asn and Asn/Asn- genotypes have a risk of arterial hypertension 2.6 (95% of SI = 1.224-5.488), and homozygotes of the minor allele (Asn/Asn) 7.3 (95% of SI = 1.295-41.639) times higher than the Lys/Lys homozygotes. CONCLUSION: Conclusions: Lys198Asn-polymorphism of the endothelin-1 gene is associated with the development of arterial hypertension in Ukrainian population. Carriers of minor allele (Lys/Asn+Asn/ Asn) have a risk of arterial hypertension 1.7, and homozygotes Asn/Asn 3.9 times higher than people with Lys/Lys genotype.


Assuntos
Endotelina-1/genética , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Ucrânia
4.
Environ Health Prev Med ; 24(1): 26, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043174

RESUMO

BACKGROUND: Hypertension and atherosclerosis are bidirectionally related, while platelet count could serve as an indicator of endothelial repair. Therefore, high platelet counts could be associated with hypertension by indicating more intense endothelial repair activity. Furthermore, short stature has been shown to constitute a risk of atherosclerosis. Since inflammation-related single-nucleotide polymorphism (SNP (rs3782886)) is reportedly associated with myocardial infarction and short stature, rs3782886 could be associated with a high platelet count and thus more intense endothelial repair activity. METHODS: We conducted a cross-sectional study of 988 elderly Japanese who participated in a general health check-up. Short stature was defined as a height of at or under the 25th percentile of the study population, and high platelet count as the highest tertiles of the platelet levels. RESULTS: High platelet counts were found to be independently and positively associated with hypertension while rs3782886 was independently associated with high platelet levels and short stature. The classical cardiovascular risk factor-adjusted odds ratio (OR) and 95% confidence interval (CI) of high platelet count for hypertension was 1.34 (1.02, 1.77). With non-minor homo of the rs3782886 as the reference group, the adjusted OR and 95% CI for high platelet count and short stature of minor home were 2.40 (1.30, 4.42) and 2.21 (1.16, 4.21), respectively. CONCLUSION: SNP (rs3782886) was shown to be associated with high platelet count and short stature. This result partly explains how a genetic factor can influence the impact of height on endothelial repair.


Assuntos
Plaquetas/metabolismo , Estatura/genética , Endotélio Vascular/fisiologia , Predisposição Genética para Doença , Hipertensão/sangue , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Contagem de Plaquetas
5.
Genet Test Mol Biomarkers ; 23(5): 342-347, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30932691

RESUMO

Objective: To investigate the association between the CYP4F2 gene rs1558139 and rs2108622 polymorphisms and hypertension. Materials and Methods: In this meta-analysis, we searched databases for case-control studies published before May 2018 examining the associations between two polymorphic sites of the CYP4F2 gene (rs1558139 and rs2108622) and hypertension. The fixed or random effects model chosen was selected according to the heterogeneity of the studies to calculate the pooled odds ratios (OR) and corresponding 95% confidence intervals (95% CI). Results: Six articles in total were analyzed in this study; three investigated the rs1558139 polymorphism and six investigated the rs2108622 polymorphism. The pooled OR and 95% CI using the dominant model for rs1558139, and both the homozygous model and the recessive model of rs2108622 were statistically significant giving values of 0.83 (0.71-0.96), 0.83 (0.71-0.98), and 1.24 (1.07-1.44), respectively. The pooled OR and 95% CI of the rs1558139 polymorphism in the subgroup analysis based on gender were 1.25 (1.08-1.45) and 0.98 (0.85-1.13), whereas the results for the rs2108622 polymorphism were 1.03 (0.86-1.24) and 0.91 (0.72-1.14). Conclusion: Our meta-analysis demonstrates that the rs1558139 and rs2108622 single nucleotide polymorphisms of the CYP4F2 gene are associated with hypertension, with a particularly strong link between the rs1558139 polymorphism in males.


Assuntos
Família 4 do Citocromo P450/genética , Hipertensão/enzimologia , Hipertensão/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , Fatores de Risco , Fatores Sexuais , Varfarina/farmacologia
6.
PLoS Genet ; 15(4): e1008060, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31022172

RESUMO

The promise of personalized genomic medicine is that knowledge of a person's gene sequences and activity will facilitate more appropriate medical interventions, particularly drug prescriptions, to reduce the burden of disease. Early successes in oncology and pediatrics have affirmed the power of positive diagnosis and are mostly based on detection of one or a few mutations that drive the specific pathology. However, genetically more complex diseases require the development of polygenic risk scores (PRSs) that have variable accuracy. The rarity of events often means that they have necessarily low precision: many called positives are actually not at risk, and only a fraction of cases are prevented by targeted therapy. In some situations, negative prediction may better define the population at low risk. Here, I review five conditions across a broad spectrum of chronic disease (opioid pain medication, hypertension, type 2 diabetes, major depression, and osteoporotic bone fracture), considering in each case how genetic prediction might be used to target drug prescription. This leads to a call for more research designed to evaluate genetic likelihood of response to therapy and a call for evaluation of PRS, not just in terms of sensitivity and specificity but also with respect to potential clinical efficacy.


Assuntos
Herança Multifatorial , Medicina de Precisão/métodos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Mutação , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Osteoporose/genética , Osteoporose/prevenção & controle , Testes Farmacogenômicos/métodos , Medicina Preventiva/métodos , Fatores de Risco
7.
Biol Pharm Bull ; 42(4): 543-546, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930414

RESUMO

Hypertension is one risk for atrial fibrillation (AF) and induces cardiac inflammation. Recent evidence indicates that pressure overload-induced ventricular structural remodeling is associated with the activation of nucleotide binding-oligomerization domain (NOD)-like receptor P3 (NLRP3) inflammasomes, including an apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). We hypothesized that NLRP3 inflammasomes are an initial sensor for danger signals in pressure overload-induced atrial remodeling, leading to AF. Transverse aortic constriction (TAC) or a sham procedure was performed in mice deficient for ASC-/- and interleukin-1ß (IL-1ß-/-). One week after the procedure, electrical left atrial burst pacing from the esophagus was performed for 30 s to induce AF. IL-1ß, monocyte chemotactic protein 1 (MCP-1), connective tissue growth factor (CTGF), and collagen 1 gene expression were also examined. The electrical burst pacing induced AF in TAC-operated wild-type (WT) (p < 0.001) and ASC-/- (p < 0.05) mice, compared to no AF in the sham-operated WT and ASC-/- mice, respectively. In contrast, the number of mice in which sustained AF was induced was similar between TAC-operated IL-1ß-/- and sham-operated IL-1ß-/- mice (p > 0.05). The expression of all genes tested was increased in TAC-operated WT and ASC-/- mice compared with sham-operated WT and ASC-/- mouse atria, respectively. CTGF and collagen 1, but not MCP-1, gene expressions were increased in TAC-operated IL-1ß-/- mouse atria compared with sham-operated WT and IL-1ß-/- mouse atria. In contrast, the IL-1ß gene was not detected in either TAC-operated or sham-operated IL-1ß-/- mouse atria. These results suggest that an IL-1ß activation pathway, different from NLRP3 inflammasomes, plays an important role in pressure overload-induced sustained AF.


Assuntos
Fibrilação Atrial/metabolismo , Hipertensão/metabolismo , Interleucina-1beta/metabolismo , Animais , Fibrilação Atrial/genética , Pressão Sanguínea , Proteínas Adaptadoras de Sinalização CARD/genética , Quimiocina CCL2/genética , Átrios do Coração/metabolismo , Hipertensão/genética , Interleucina-1beta/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
8.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945668

RESUMO

The aim of this study was to determine whether the polymorphism of aldosterone synthase (CYP11B2) -344C/T and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) were associated with the response of blood pressure (BP) to telmisartan treatment. After a two-week single-blind placebo run-in period, 148 patients with mild-to-moderate primary hypertension received monotherapy of telmisartan with 80 mg/day and then were followed up for eight weeks. Polymorphisms of CYP11B2 -344C/T and ACE I/D gene were determined through polymerase chain reaction-restriction fragment polymorphism analysis. The relationship between these polymorphisms and changes in BP was monitored and evaluated after eight weeks of treatment. With respect tothe polymorphism of CYP11B2 -344C/T, the reduction in diastolic BP was significantly greater in patients carrying the C allele (CC+CT) compared with those carrying the TT genotype. There was no significant differences between ACE I/D polymorphism and BP reduction after treatment. We concluded that the aldosterone synthase -344C/T polymorphism was related to the antihypertensive treatment with telmisartan in hypertensive patients.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Pressão Sanguínea , Citocromo P-450 CYP11B2/genética , Hipertensão/genética , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Telmisartan/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Seguimentos , Genótipo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Método Simples-Cego , Adulto Jovem
9.
J Med Food ; 22(4): 393-407, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30990753

RESUMO

Although leaves of Anchietea salutaris are used in Brazilian traditional medicine, there is no available data in the literature proving its efficacy and safety. Thus, the aim of the study was to perform a meticulous botanical, phytochemical, toxicological, and pharmacological investigation of A. salutaris in Wistar rats. At first, a morphoanatomical characterization of Anchietea pyrifolia leaves and stems was performed. Then, a purified infusion (ethanol-soluble fraction obtained from A. pyrifolia [ESAP]) was obtained followed by its chemical profile elucidation. Furthermore, an acute toxicity test was performed, and the acute and prolonged diuretic and hypotensive effects were also evaluated in Wistar rats. Finally, the vasodilatory responses of ESAP in mesenteric vascular beds were investigated. The main secondary metabolites identified from ESAP were O-glycosylated flavonoids, chlorogenic acids, and phenylpropanoic acid derivatives. ESAP did not promote any toxic effects in female rats nor increased urinary excretion in male rats after a single exposure. However, ESAP significantly reduced renal elimination of sodium, potassium, and chloride after prolonged treatment. An ESAP highest dose promoted significant acute hypotension without affecting blood pressure levels after prolonged use. Furthermore, its cardiovascular effects seem to be related with the calcium-activated potassium channel activation in resistance vessels.


Assuntos
Anti-Hipertensivos/administração & dosagem , Hipertensão/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Violaceae/química , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/química , Pressão Sanguínea/efeitos dos fármacos , Brasil , Diuréticos/administração & dosagem , Diuréticos/efeitos adversos , Diuréticos/química , Feminino , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Folhas de Planta/química , Canais de Potássio Cálcio-Ativados/genética , Canais de Potássio Cálcio-Ativados/metabolismo , Ratos Wistar
10.
Med Sci Monit ; 25: 2633-2639, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30968846

RESUMO

BACKGROUND This study investigated the expression of the BCL2 and BAX mRNA, inflammatory cytokines, interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-alpha), and cardiac function in patients with chronic heart failure (CHF). The New York Heart Association (NYHA) Functional Classification and measurement of the left ventricular ejection fraction (LVEF) evaluated cardiac function. MATERIAL AND METHODS Patients with CHF (n=60) due to coronary heart disease, hypertensive heart disease, and cardiomyopathy, and healthy controls (n=30) were studied. Enzyme-linked immunosorbent assay (ELISA) measured serum levels of IL-1ß, IL-6, and TNF-alpha. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected mRNA expression of BCL2 and BAX in peripheral blood mononuclear cells (PBMCs). Color Doppler ultrasound measured the LVEF, and the NYHA classification of CHF was used. RESULTS In patients with CHF, levels of IL-1ß, IL-6 and TNF-alpha, and mRNA expression of BAX were significantly increased compared with the control group (p<0.01); BCL2 mRNA level was significantly lower (p<0.01). There were no significant differences in the expression levels of inflammatory cytokines, or BCL2 or BAX mRNA in patients with CHF due to coronary heart disease, hypertensive heart disease, or cardiomyopathy. Expression levels of IL-1ß, IL-6, TNF-alpha, and BAX mRNA were significantly associated with the degree of CHF. Cardiac function was negatively correlated with LVEF (p<0.05). Expression levels of BCL2 mRNA level were negatively correlated with cardiac function (p<0.05), and positively correlated with LVEF (p<0.05). CONCLUSIONS Levels of IL-1ß, IL-6, TNF-alpha, and BAX mRNA were negatively correlated with cardiac function, and BCL2 mRNA expression was positively associated with CHF.


Assuntos
Citocinas/sangue , Regulação da Expressão Gênica , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , Mediadores da Inflamação/sangue , Leucócitos Mononucleares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Idoso , Cardiomiopatias/sangue , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Doença Crônica , Doença das Coronárias/sangue , Doença das Coronárias/genética , Doença das Coronárias/fisiopatologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Humanos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Volume Sistólico , Proteína X Associada a bcl-2/sangue
11.
Front Biosci (Schol Ed) ; 11: 136-160, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844741

RESUMO

African-American (AA) women are more likely to die from breast cancer (BC), at any age, compared to European-American women. Although breakthroughs in pre-clinical studies have resulted in potentially actionable targets in AA BC, drugs that were rationally designed for these targets have performed poorly in clinical trials. Challenges with interpatient and intratumoral heterogeneity, lack of drug sensitivity and specificity, suboptimal biomarker cut-offs, lack of drug response predictive biomarkers, drug side effects, high costs of drug development, and under-representation of AAs in clinical trials complicate the development of targeted therapies for AA BC patients. Accumulating evidence suggests that racial disparities exist in non-genetic risk factors that can alter genetic and epigenetic programs to promote breast tumorigenesis. Herein, we present a "roadmap" that addresses non-genetic risk factors that are suspected to contribute to the racial disparity in BC mortality. Increased targeting of these non-genetic risk factors may proffer a safer and more economical route to alleviating the racially disparate burden in BC.


Assuntos
Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Afro-Americanos/genética , Consumo de Bebidas Alcoólicas , Biomarcadores , Tamanho Corporal , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Características Culturais , Diabetes Mellitus/etnologia , Diabetes Mellitus/genética , Escolaridade , Disruptores Endócrinos , Grupo com Ancestrais do Continente Europeu/genética , Medo , Feminino , Disparidades nos Níveis de Saúde , Terapia de Reposição Hormonal , Humanos , Hipertensão/complicações , Hipertensão/etnologia , Hipertensão/genética , Seguro Saúde , Estilo de Vida , Menarca , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/etnologia , Obesidade/genética , Religião , Características de Residência , Fatores de Risco , Sono , Estresse Psicológico , Transportes
12.
Int J Mol Sci ; 20(5)2019 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-30832344

RESUMO

Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (SCNN1B), Armadillo Repeat Containing 5 (ARMC5), G Protein-Coupled Receptor Kinase 4 (GRK4), and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure.


Assuntos
Afro-Americanos/genética , Hipertensão/genética , Canais de Cálcio Tipo L/genética , Canais Epiteliais de Sódio/genética , Quinase 4 de Receptor Acoplado a Proteína G/genética , Humanos , Hipertensão/etnologia , Proteínas Supressoras de Tumor/genética
13.
Environ Health Prev Med ; 24(1): 19, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30857519

RESUMO

Risk factors for hypertension consist of lifestyle and genetic factors. Family history and twin studies have yielded heritability estimates of BP in the range of 34-67%. The most recent paper of BP GWAS has explained about 20% of the population variation of BP. An overestimation of heritability may have occurred in twin studies due to violations of shared environment assumptions, poor phenotyping practices in control cohorts, failure to account for epistasis, gene-gene and gene-environment interactions, and other non-genetic sources of phenotype modulation that are suspected to lead to underestimations of heritability in GWAS. The recommendations of hypertension guidelines in major countries consist of the following elements: weight reduction, a healthy diet, dietary sodium reduction, increasing physical activity, quitting smoking, and moderate alcohol consumption. The hypertension guidelines are mostly the same for each country or region, beyond race and culture. In this review, we summarize gene-environmental interactions associated with hypertension by describing lifestyle modifications according to the hypertension guidelines. In the era of precision medicine, clinicians who are responsible for hypertension management should consider the gene-environment interactions along with the appropriate lifestyle components toward the prevention and treatment of hypertension. We briefly reviewed the interaction of genetic and environmental factors along the constituent elements of hypertension guidelines, but a sufficient amount of evidence has not yet accumulated, and the results of genetic factors often differed in each study.


Assuntos
Interação Gene-Ambiente , Hipertensão/terapia , Estilo de Vida , Guias de Prática Clínica como Assunto , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Hipertensão/prevenção & controle , Medicina de Precisão/normas , Fatores de Risco
14.
DNA Cell Biol ; 38(5): 449-456, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30839233

RESUMO

Intracerebral hemorrhage (ICH) represents the most lethal form of stroke. We sought to identify potential genes that might contribute to progression of hypertension-induced spontaneous ICH (HIS-ICH). RNA-sequencing data set of cerebral vessel samples from HIS-ICH mice and normal mice was obtained from the Gene Expression Omnibus. Differential expression genes in HIS-ICH samples were obtained compared with normal samples followed by functional enrichment analysis. What is more, we explored the potential gene coexpression module (GCM) for HIS-ICH progression by using weighted gene coexpression network analysis. We further conducted protein-protein interaction network analysis for genes contained in GCM that was closely correlated with HIS-ICH to disclose their biological interactions. As a result, 554 genes were found to aberrantly express in HIS-ICH mice compared with normal mice, which were mainly associated with cancer-related pathways in addition to some well-known ICH-related pathways. A total of 28 GCMs were obtained, and darkturquoise module that contained 85 genes, which were closely associated with mitochondrion and hydrolase activity, was significantly correlated with HIS-ICH progression. Besides, we identified dense biological interactions among some genes in darkturquoise, such as Psma gene family and Hsp90a gene family. This study should shed new light on HIS-ICH progression and its treatment.


Assuntos
Hemorragia Cerebral/genética , Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Hipertensão/genética , Animais , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Camundongos , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Análise de Sequência de RNA
15.
J Strength Cond Res ; 33(4): 1119-1129, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30908459

RESUMO

Montrezol, FT, Marinho, R, Mota, GdFAd, D'almeida, V, de Oliveira, EM, Gomes, RJ, and Medeiros, A. ACE gene plays a key role in reducing blood pressure in the hyperintensive elderly after resistance training. J Strength Cond Res 33(4): 1119-1129, 2019-Hypertension is a difficult disease to control and exercise training plays a key role in hypertension control. Some individuals are not responsive to exercise training; so, we highlight the polymorphism of I allele of angiotensin-converting enzyme (ACE) as a factor responsible for this lack of responsiveness. The aim of this study was to evaluate the influence of ACE insertion/deletion genotypes on effects of resistance training on blood pressure (BP) and chronic inflammation. Eighty-six hypertensive volunteers, aged between 60 and 80, were evaluated. They performed 16 weeks of resistance training at 50% of 1 maximal repetition. The greatest benefits were seen on homozygous of the Insertion allele, whom presented reduction of systolic blood pressure (SBP: 129.31 ± 13.34 vs. 122.56 ± 9.68 mm Hg, p < 0.001) and diastolic blood pressure (DBP: 79.18 ± 8.05 vs. 70.12 ± 7.71 mm Hg, p < 0.01) during daytime period, and in 24-hour period (SBP: 127.12 ± 13.65 vs. 121.06± 9.68 mm Hg, p < 0.001 and DBP: 71.87 ± 8.39 vs. 68.75 ± 8.72 mm Hg, p < 0.05) and also increased circulating adiponectin levels (4.04 ± 1.79 vs. 6.00 ± 2.81 ng·ml, p < 0.01). Other genotypes showed no changes in BP and biochemical parameters. Our results suggest a cardio protective factor of I allele because only those homozygous showed reductions in BP and increases in adiponectin.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Hipertensão/fisiopatologia , Peptidil Dipeptidase A/genética , Treinamento de Resistência , Adiponectina/sangue , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença Crônica , Exercício/fisiologia , Feminino , Homozigoto , Humanos , Hipertensão/sangue , Mutação INDEL , Inflamação/sangue , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
16.
Life Sci ; 225: 39-45, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30917908

RESUMO

AIMS: Renin-angiotensin system modulates cardiac structure independent of blood pressure. The present study aimed at investigating whether single nucleotide polymorphism (SNP) and haplotype of angiotensin converting enzyme 2 (ACE2) could influence blood pressure and the susceptibility to hypertensive left ventricular hypertrophy (LVH). SUBJECTS AND METHODS: A total of 647 patients (347 females and 300 males) with newly diagnosed mild to moderate essential hypertension were enrolled in a blood pressure matched, case-control study. Four ACE2 tagSNPs (rs2074192, rs4646176, rs4646155 and rs2106809) were genotyped and major haplotypes consisting of these four SNPs were reconstructed for all subjects. KEY FINDINGS: In females, minor alleles of ACE2 rs2074192 and rs2106809 respectively conferred a 2.1 and 2.0 fold risk for LVH. ACE2 haplotype TCGT increased the risk for LVH while another haplotype CCGC decreased the risk in females. The covariates-adjusted mean left ventricular mass index was 11% greater in TCGT haplotype carriers than in noncarriers in women. In females, the covariates-adjusted mean systolic blood pressure was 3.4 mm Hg lower in CCGC haplotype carriers than in noncarriers. In males, the covariates-adjusted mean systolic blood pressure was 2.4 mm Hg lower in CCGC haplotype carriers than in noncarriers. SIGNIFICANCE: ACE2 tagSNPs rs2074192 and rs2106809 as well as major haplotypes CCGC and TCGT may serve as novel risk markers for LVH in hypertensive patients.


Assuntos
Marcadores Genéticos , Hipertensão/genética , Hipertrofia Ventricular Esquerda/genética , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Hipertensão/patologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Zhonghua Nei Ke Za Zhi ; 58(4): 278-281, 2019 Apr 01.
Artigo em Chinês | MEDLINE | ID: mdl-30917420

RESUMO

Objective: To analyze the relationship between the level of microRNA-29b in circulation and left ventricular hypertrophy in hypertensive patients. Methods: A total of 240 subjects from Henan Province People's Hospital from June 2015 to June 2018 were included in the present study. Among them, 160 were hospitalized patients, and were divided into two groups. Patients with simple hypertension and had no left ventricular hypertrophy (80 cases) were in the simple hypertension group (HBP-NLVH), and patients with hypertension combined with left ventricular hypertrophy (80 cases) were in the high blood pressure with left ventricular hypertrophy group (HBP-LVH). Normal control subjects (80 cases) were those with no hypertension and randomly selected from the medical center of Henan Province People's Hospital. Serum microRNA-29b expressions were detected by real time fluorescence quantitative PCR. The thickness of interventricular septum (IVSD) and left ventricular posterior wall thickness (LVPWD) were measured by echocardiography. Results: Compared with the normal control group (1.95±0.79), the relative expression of microRNA-29b in the patients both in the HBP-NLVH group (2.67±0.92) and the HBP-LVH group (5.12±1.23) was up-regulated, and the difference between normal control and patients was statistically significant (P<0.05). In patients, the microRNA-29b level in the HBP-LVH group was significantly higher than that in the HBP-NLVH group (P<0.05). The expression level of microRNA-29b was positively correlated with IVSD (r=0.71, P<0.05) and LVPWD (r=0.74, P<0.05), respectively. The sensitivity and specificity of serum microRNA-29b levels in the diagnosis of left ventricular hypertrophy in hypertension patients were 96.8% and 91.3%, respectively. Conclusion: Serum microRNA-29b level is elevated in hypertensive patients with left ventricular hypertrophy, and is positively correlated with left ventricular hypertrophy. The circulation microRNA-29b might be a useful biomarker with prognostic value in left ventricular hypertrophy in hypertension patients.


Assuntos
Hipertensão , Hipertrofia Ventricular Esquerda , MicroRNAs/genética , MicroRNA Circulante , Ecocardiografia , Humanos , Hipertensão/genética , Prognóstico
18.
Diab Vasc Dis Res ; 16(1): 13-21, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789093

RESUMO

OBJECTIVES: The aim of this study is to explore the contribution of genetically driven cardiometabolic risk factors for development of carotid arterial thickening in patients with type 2 diabetes. METHODS: In total, 12 genetic risk scores for blood pressure, blood lipids and glycaemic traits were constructed. The genetic risk scores were tested for association with carotid intima-media thickness and plaques in patients with type 2 diabetes ( n = 401) and in non-diabetic individuals ( n = 648) and for association with glucose levels in two population-based cohorts ( n = 1328 and n = 6161). RESULTS: In patients with type 2 diabetes, the genetic risk scores for pulse pressure were positively associated with plaque formation ( ß = 0.036 ± 0.01 standard deviation/allele, p = 0.003). The genetic risk score for diastolic blood pressure was negatively associated with carotid intima-media thickness ( ß = -0.037 ± 0.01 standard deviation/allele, p = 0.005), although not significant after correction for multiple testing ( p < 0.0042). In a meta-analysis of individuals with and without type 2 diabetes, the high-density lipoprotein genetic risk scores showed a trend towards an inverse association with carotid intima-media thickness and plaques, while the low-density lipoprotein genetic risk scores showed a trend towards a positive association with plaque formation but did reach the statistical threshold. CONCLUSION: Genetic loci for pulse pressure are associated with plaque formation among patients with type 2 diabetes, suggesting an underlying genetic contribution to arterial stiffening and atherosclerosis.


Assuntos
Pressão Sanguínea/genética , Doenças das Artérias Carótidas/genética , Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2/genética , Hipertensão/genética , Placa Aterosclerótica , Locos de Características Quantitativas , Característica Quantitativa Herdável , Idoso , Doenças das Artérias Carótidas/diagnóstico por imagem , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco
19.
In Vivo ; 33(2): 559-562, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30804141

RESUMO

The association of the high blood pressure D variant of the angiotensin-converting enzyme (ACE) gene with medication-related jaw osteonecrosis (MRONJ) is described in two Greek patients. The first patient, a 73-year-old man, took zolendronate, 4 mg/100 ml IV once per month for two years for prostate cancer and bone metastases. Three months after drug discontinuation, extraction of the first premolar was performed. After the intervention, he suffered from osteonecrosis of the mandible. He presented with hypertension and genetic testing revealed that he was homozygous for the high blood pressure D variant of the ACE gene. The second patient, a 65 years old woman, took denosumab, 120 mg subcutaneously once per month for 6 months for possible bone metastases from breast cancer. Three months after extraction of the first molar, she suffered from MRONJ. He also presented with hypertension and genetic testing revealed that she had the high blood pressure D variant of the ACE gene in a heterozygous state, which moderately predisposes to hypertension. To our knowledge, this is the first report indicating that genetic predisposition to hypertension may increase risk for MRONJ.


Assuntos
Hipertensão/genética , Doenças Maxilomandibulares/genética , Osteonecrose/genética , Peptidil Dipeptidase A/genética , Idoso , Denosumab/efeitos adversos , Testes Genéticos , Heterozigoto , Humanos , Hipertensão/etiologia , Hipertensão/patologia , Doenças Maxilomandibulares/induzido quimicamente , Doenças Maxilomandibulares/complicações , Doenças Maxilomandibulares/patologia , Masculino , Metástase Neoplásica , Osteonecrose/induzido quimicamente , Osteonecrose/complicações , Osteonecrose/patologia , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Ácido Zoledrônico/efeitos adversos
20.
Proc Natl Acad Sci U S A ; 116(8): 3155-3160, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718414

RESUMO

Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3S433-P) via protein kinase C, resulting in increased WNK4 levels and increased NCC activity. Mechanisms mediating KLHL3S433-P dephosphorylation have heretofore been unknown. We now demonstrate that calcineurin expressed in DCT is a potent KLHL3S433-P phosphatase. In mammalian cells, the calcium ionophore ionomycin, a calcineurin activator, reduces KLHL3S433-P levels, and this effect is reversed by the calcineurin inhibitor tacrolimus and by siRNA-mediated knockdown of calcineurin. In vivo, tacrolimus increases levels of KLHL3S433-P, resulting in increased levels of WNK4, phosphorylated SPAK, and NCC. Moreover, tacrolimus attenuates KLHL3-mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution. Additionally, increased extracellular K+ induced calcineurin-dependent dephosphorylation of KLHL3S433-P These findings demonstrate that KLHL3S433-P is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.


Assuntos
Proteínas de Transporte/genética , Hipertensão/genética , Proteínas Serina-Treonina Quinases/genética , Insuficiência Renal/genética , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Calcineurina/genética , Inibidores de Calcineurina/administração & dosagem , Proteínas Culina/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Mutação em Linhagem Germinativa/genética , Humanos , Hiperpotassemia/genética , Hiperpotassemia/metabolismo , Hiperpotassemia/patologia , Hipertensão/metabolismo , Hipertensão/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/patologia , Camundongos , Complexos Multiproteicos/genética , Fosforilação , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Tacrolimo/toxicidade , Ubiquitinação
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