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OBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.
Assuntos
Contactinas/genética , Gota/genética , Hiperuricemia/genética , MicroRNAs/genética , Dedos de Zinco/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Aldeído-Desidrogenase Mitocondrial/genética , Doenças Assintomáticas , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Fatores de Risco , Ácido Úrico/sangueRESUMO
RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Variação Genética/genética , Adulto , Idoso , Estudos de Casos e Controles , Proteínas de Transferência de Ésteres de Colesterol/sangue , Doença das Coronárias/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10(-4)), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10(-4)) and body mass index (BMI)-adjusted waist-hip ratio (P = 9.8 × 10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.
Assuntos
Adiponectina/sangue , Doenças Cardiovasculares/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Povo Asiático , Doenças Cardiovasculares/sangue , Estudos de Coortes , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIMS/HYPOTHESIS: To investigate epigenetic regulation of the plasma concentration of resistin, we performed an epigenome-wide association study for this variable and DNA methylation (DNAm) in an elderly Japanese cohort and then assessed the relation of single nucleotide polymorphisms (SNPs) associated with the plasma resistin concentration to DNAm level at identified sites. METHODS: The association of plasma resistin level with DNAm status was examined in 191 nondiabetic elderly men with the Illumina Infinium HumanMethylation450 BeadChip array. The association between DNAm status at specific sites in the flanking region of the resistin gene (RETN) and RETN mRNA abundance was then evaluated with a public data set for 1202 monocyte samples from a multi-ethnic cohort. Finally, the association of DNAm status and SNPs in the promoter region of RETN was assessed in two cohorts comprising a total of 478 Japanese individuals. RESULTS: DNAm status at cg02346997 located in the RETN promoter region showed a negative genome-wide significant association with the plasma resistin level (p = 6.02 × 10(-10)). Four DNAm sites in the RETN promoter region including cg02346997 (p = 4.23 × 10(-70)) showed a negative genome-wide significant association with RETN mRNA abundance in monocytes. Furthermore, the number of minor alleles of the RETN promoter SNPs rs34861192 and rs3219175 was negatively associated with DNAm level at cg02346997 (p = 4.43 × 10(-17)). CONCLUSIONS/INTERPRETATION: Our results suggest that RETN promoter SNPs might influence the circulating resistin level through an effect on DNAm at cg02346997 and on RETN mRNA abundance in monocytes.
Assuntos
Epigênese Genética/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Resistina/genética , Resistina/metabolismo , Idoso , Alelos , Povo Asiático , Estudos Transversais , Metilação de DNA , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genéticaRESUMO
BACKGROUND: A coronary artery disease (CAD) association study of genetic loci previously identified as being associated with blood pressure (BP) was performed in east Asian populations. METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) from 9 candidate loci robustly confirmed to be associated with BP in east Asian people, were genotyped. Genotyping was done in up to 17,785 CAD case-control samples (6,522 cases and 11,263 controls). We then tested the associations with other metabolic traits (n≤17,900) and with type 2 diabetes (931 cases and 1,404 controls), and looked up the datasets in silico in other populations. Significant (adjusted P<0.05) CAD associations were found for 5 BP loci: 3 new CAD associations at FIGN,FGF5 and NPR3, and 2 previously reported ones at ATP2B1 and CNNM2. The strongest CAD association was detected at ATP2B1rs2681472 (P=1.7×10(-8)), in the direction inverted to what is generally recognized for BP in the epidemiological studies.CNNM2rs12413409 showed significant association with CAD (P=8.7×10(-7)) and BMI (P=3.5×10(-8), when meta-analyzed with 75,807 east Asian people). The genetic risk score combining BP-raising alleles at each of the SNPs was positively associated with CAD (P=0.011). CONCLUSIONS: A substantial proportion of genetic variants associated with BP were also associated with the risk of CAD in east Asian people, and there was some counter-evidence for causal inference.
Assuntos
Pressão Sanguínea/genética , Doença da Artéria Coronariana/genética , Ciclinas/genética , Loci Gênicos , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Povo Asiático , Proteínas de Transporte de Cátions , Doença da Artéria Coronariana/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Genome-wide association studies have identified many genetic loci associated with blood pressure (BP). Genetic effects on BP can be altered by environmental exposures via multiple biological pathways. Especially, obesity is one of important environmental risk factors that can have considerable effect on BP and it may interact with genetic factors. Given that, we aimed to test whether genetic factors and obesity may jointly influence BP. METHODS: We performed meta-analyses of genome-wide association data for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that included analyses of interaction between single nucleotide polymorphisms (SNPs) and the obesity-related anthropometric measures, body mass index (BMI), height, weight, and waist/hip ratio (WHR) in East-Asians (n = 12,030). RESULTS: We identified that rs13390641 on 2q12.1 demonstrated significant association with SBP when the interaction between SNPs and BMI was considered (P < 5 × 10 -8). The gene located nearest to rs13390641, TMEM182, encodes transmembrane protein 182. In stratified analyses, the effect of rs13390641 on BP was much stronger in obese individuals (BMI ≥ 30) than non-obese individuals and the effect of BMI on BP was strongest in individuals with the homozygous A allele of rs13390641. CONCLUSIONS: Our analyses that included interactions between SNPs and environmental factors identified a genetic variant associated with BP that was overlooked in standard analyses in which only genetic factors were included. This result also revealed a potential mechanism that integrates genetic factors and obesity related traits in the development of high BP.
Assuntos
Povo Asiático/genética , Pressão Sanguínea/genética , Cromossomos Humanos Par 2 , Interação Gene-Ambiente , Variação Genética , Estudo de Associação Genômica Ampla , Índice de Massa Corporal , Estudos de Associação Genética , Genótipo , Humanos , Obesidade/genética , Obesidade/fisiopatologia , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. To maximize the coverage of the genome, imputation was performed based on 1000 Genome JPT+CHB and 5.1 million SNPs were retained. CAD association was replicated for three GWAS-identified loci (1p13.3/SORT1 (rs599839), 9p21.3/CDKN2A/2B (rs4977574), and 11q22.3/ PDGFD (rs974819)) in Koreans. From GWAS and a replication, SNP rs3782889 showed a strong association (combined P=3.95 × 10(-14)), although the association of SNP rs3782889 doesn't remain statistically significant after adjusting for SNP rs11066015 (proxy SNP with BRAP (r(2)=1)). But new possible CAD-associated variant was observed for rs9508025 (FLT1), even though its statistical significance did marginally reach at the genome-wide a significance level (combined P=6.07 × 10(-7)). This study shows that three CAD susceptibility loci, which were previously identified in European can be directly replicated in Koreans and also provides additional evidences implicating suggestive loci as risk variants for CAD in East Asian.
Assuntos
Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Loci Gênicos , Predisposição Genética para Doença , Genoma Humano , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Two consortium-based genome-wide association studies have recently identified robust and significant associations of common variants with systolic and diastolic blood pressures in populations of European descent, warranting further investigation in populations of non-European descent. METHODS AND RESULTS: We examined the associations at 27 loci reported by the genome-wide association studies on Europeans in a screening panel of Japanese subjects (n=1526) and chose 11 loci showing association signals (1-tailed test in the screening, P<0.3) for an extensive replication study with a follow-up panel of 3 Japanese general-population cohorts (n < or =24 300). Significant associations were replicated for 7 loci-CASZ1, MTHFR, ITGA9, FGF5, CYP17A1-CNNM2, ATP2B1, and CSK-ULK3-with any or all of these 3 traits: systolic blood pressure (P=1.4x10(-14) to 0.05), diastolic blood pressure (P=1.9x10(-12) to 0.05), and hypertension (P=2.0x10(-14) to 0.006; odds ratio, 1.10 to 1.29). The strongest association was observed for FGF5. In the whole study panel, the variance (R(2)) for blood pressure explained by the 7 single-nucleotide polymorphism loci was calculated to be R(2)=0.003 for male and 0.006 for female participants. Stratified analysis implied the potential presence of a gene-age-sex interaction, although it did not reach a conclusive level of statistical significance after adjustment for multiple testing. CONCLUSIONS: We have confirmed 7 loci associated with blood pressure and/or hypertension in the Japanese. These loci can guide fine-mapping efforts to pinpoint causal variants and causal genes with the integration of multiethnic results.
Assuntos
Povo Asiático/genética , Pressão Sanguínea/genética , Loci Gênicos/genética , Hipertensão/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/etnologia , Estudos Transversais , Proteínas de Ligação a DNA/genética , Feminino , Fator 5 de Crescimento de Fibroblastos/genética , Humanos , Integrinas/genética , Japão , Masculino , Pessoa de Meia-Idade , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/genética , Esteroide 17-alfa-Hidroxilase/genética , Fatores de Transcrição/genética , Adulto JovemRESUMO
Coronary artery spasm has an important function in the etiology of variant angina and other acute coronary syndromes. Abnormal activation of Rho-family GTPases has been observed in cardiovascular disorders, but the function of genetic variability in Rho-family GTPases remains to be evaluated in cardiovascular disorders. We examined the genetic variability of Rho-family GTPases and their regulators in coronary artery spasm. We performed a comprehensive candidate gene analysis of 67 single nucleotide polymorphisms with amino-acid substitution in Rho-family GTPases and their regulators in 103 unrelated Japanese patients with acetylcholine-induced coronary artery spasm and 102 control Japanese subjects without acetylcholine-induced coronary artery spasm. We noted an association of the single nucleotide polymorphism of ARHGAP9 (rs11544238, Ala370Ser) with coronary artery spasm (odds ratio =2.67). We found that ARHGAP9 inactivated Rac as RacGAP and that the mRNA level of ARHGAP9 was strongly detected in hematopoietic cells. ARHGAP9 negatively regulated cell migration. The Ala370Ser polymorphism counteracted ARHGAP9-reduced cell migration, spreading and adhesion. The Ala370Ser polymorphism in the ARHGAP9 gene is associated with coronary artery spasm. These data suggest that the polymorphism of ARHGAP9 has a critical function in the infiltration of hematopoietic cells into the endothelium and inflammation leading to endothelial dysfunction.
Assuntos
Vasoespasmo Coronário/genética , Proteínas Ativadoras de GTPase/genética , Predisposição Genética para Doença , Mutação , Acetilcolina/administração & dosagem , Angina Pectoris Variante/genética , Angina Pectoris Variante/fisiopatologia , Angiografia Coronária , Vasoespasmo Coronário/induzido quimicamente , Vasoespasmo Coronário/fisiopatologia , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Células HeLa , Humanos , Japão , Células Jurkat , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Growth hormone-releasing peptide (GHRP) may act directly on the myocardium and improve left ventricular (LV) function, suggesting a potential new approach to the treatment of cardiomyopathic hearts. The present study tested the hypothesis that the beneficial cardiac effects of GHRP might include attenuation of myocardial oxidative stress. METHODS AND RESULTS: Dilated cardiomyopathic TO-2 hamsters were injected with GHRP-2 (1 mg/kg) or saline from 6 to 12 weeks of age. F1B hamsters served as controls. Untreated TO-2 hamsters progressively developed LV dilation, wall thinning, and systolic dysfunction between 6 and 12 weeks of age. Marked myocardial fibrosis was apparent in untreated hamsters at 12 weeks of age in comparison with F1B controls. The ratio of reduced to oxidized glutathione (GSH/GSSG) was decreased and the concentration of 4-hydroxynonenal (4-HNE) was increased in the hearts of untreated TO-2 hamsters. Treatment with GHRP-2 attenuated the progression of LV remodeling and dysfunction, as well as myocardial fibrosis, in TO-2 hamsters. GHRP-2 also inhibited both the decrease in the GSH/GSSG ratio and the increase in the concentration of 4-HNE in the hearts of TO-2 hamsters. CONCLUSIONS: GHRP-2 can suppress the increase in the level of myocardial oxidative stress, leading to attenuation of progressive LV remodeling and dysfunction in dilated cardiomyopathic hamsters. (Circ J 2010; 74: 163 - 170).
Assuntos
Cardiomiopatia Dilatada/metabolismo , Miocárdio/metabolismo , Oligopeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Disfunção Ventricular Esquerda/metabolismo , Aldeídos/metabolismo , Animais , Cardiomiopatia Dilatada/genética , Cricetinae , Modelos Animais de Doenças , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , Mesocricetus , Mutação , Sarcoglicanas/genética , Superóxido Dismutase/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologiaRESUMO
A numerical approach is presented to analyze the two-dimensional scattering properties from a multilayered periodic dielectric structure of an arbitrary number of arbitrarily shaped unit cells. The approach is enhanced by the periodic moment method, the lattice sums technique, and the Poisson summation formula. The matrix element's evaluation accounts for the overall coupling between layers. The choosing of lattice parameters allows designs for a wide range of applications, including the electromagnetic bandgap filtering of an E-polarized wave, which is simulated and reported here.
RESUMO
AIMS: To examine the relation between mitochondrial dysfunction and myocardial contractile and relaxation reserves in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Thirty HCM patients (LVEF >or=60%) underwent biventricular cardiac catheterization analysis both at rest and during atrial pacing as well as myocardial (99m)Tc-sestamibi scintigraphy at rest to calculate washout rate. Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy. The HCM patients were divided into two groups-group A: normal force-frequency relation and a pressure half-time (T(1/2)) of <30 ms (n = 15); group B: abnormal force-frequency relation or T(1/2) of >or=30 ms (n = 15). The (99m)Tc-sestamibi washout rate was significantly correlated with T(1/2) for all patients (r = 0.74, P < 0.01) and was also significantly greater in group B (29.2 +/- 6.3%) than in group A (19.3 +/- 3.1%). The abundance of mRNAs for mitochondrial electron transport-related enzymes was significantly higher in group A than in group B. Mitochondria showed a greater variation in size and were more disorganized in group B than in group A. CONCLUSION: Mitochondria showed functional impairment and morphological disorganization in the left ventricle of HCM patients without baseline systolic dysfunction. These mitochondrial changes were associated with impaired myocardial contractile and relaxation reserves.
Assuntos
Cardiomiopatia Hipertrófica/fisiopatologia , Mitocôndrias Cardíacas/fisiologia , Contração Miocárdica/fisiologia , Disfunção Ventricular Esquerda/fisiopatologia , Cateterismo Cardíaco , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/diagnóstico por imagem , Mitocôndrias Cardíacas/patologia , Imagem de Perfusão do Miocárdio/métodos , Descanso/fisiologia , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/patologiaRESUMO
Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that induces myocardial growth in response to several physiological and pathological stimuli. Calcineurin inhibition, induced either via cyclosporine or genetically, can decrease myocardial hypertrophy secondary to pressure overload without affecting left ventricular (LV) systolic function. Since hypertrophy can also affect LV diastolic function, the goal of this study was to examine the effects of chronic pressure overload (2 wk aortic banding) in transgenic (Tg) mice overexpressing Zaki-4beta (TgZ), a specific endogenous inhibitor of calcineurin, on LV diastolic function. As expected, in the TgZ mice with calcineurin inhibitor overexpression, aortic banding reduced the degree of LV hypertrophy, as assessed by LV weight-to-body weight ratio (3.5 + or - 0.1) compared with that in non-Tg mice (4.6 + or - 0.2). LV systolic function remained compensated in both groups with pressure overload. However, the LV end-diastolic stress-to-LV end-diastolic dimension ratio, an index of diastolic stiffness and LV pressure half-time and isovolumic relaxation time, two indexes of isovolumic relaxation, increased significantly more in TgZ mice with aortic banding. Protein levels of phosphorylated phospholamban (PS16), sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, phosphorylated ryanodine receptor, and the Na(+)/Ca(2+) exchanger were also reduced significantly (P < 0.05) in the banded TgZ mice. As expected, genetic calcineurin inhibition inhibited the development of LV hypertrophy with chronic pressure overload but also induced LV diastolic dysfunction, as reflected by both impaired isovolumic relaxation and increased myocardial stiffness. Thus genetic calcineurin inhibition reveals a new mechanism regulating LV diastolic function.
Assuntos
Inibidores de Calcineurina , Diástole , Hipertrofia Ventricular Esquerda/prevenção & controle , Miocárdio/enzimologia , Proteínas/metabolismo , Disfunção Ventricular Esquerda/enzimologia , Animais , Aorta/cirurgia , Calcineurina/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diástole/genética , Modelos Animais de Doenças , Elasticidade , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular , Ligadura , Camundongos , Camundongos Transgênicos , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Fosforilação , Proteínas/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Volume Sistólico , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Pressão VentricularRESUMO
The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age. Cathepsin expression and activity were increased in the left ventricle of HF rats; olmesartan inhibited these effects, restored the balance between elastin and collagen in the left ventricle, and suppressed degradation of the elastic lamina of coronary arteries of HF rats. Furthermore, olmesartan inhibited up-regulation of NADPH oxidase subunits and activity as well as superoxide generation. These effects of olmesartan were mimicked by E64d and were accompanied by amelioration of cardiac fibrosis. Finally, olmesartan and apocynin reduced angiotensin II-induced increases in cathepsin mRNA and protein levels in cultured rat neonatal cardiac myocytes. These data suggest that cathepsins likely trigger and promote cardiac remodeling and that blocking the angiotensin II type 1 receptor attenuates cathepsin expression and activity by inhibiting the production of superoxide by NADPH oxidase, thereby attenuating cardiac remodeling and dysfunction.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Catepsinas/metabolismo , Insuficiência Cardíaca/metabolismo , Imidazóis/farmacologia , Miocárdio/metabolismo , Superóxidos/metabolismo , Tetrazóis/farmacologia , Animais , Catepsinas/antagonistas & inibidores , Células Cultivadas , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Humanos , Hipertensão/complicações , Leucina/análogos & derivados , Leucina/farmacologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NADPH Oxidases/metabolismo , Ratos , Ratos Endogâmicos Dahl , Receptor Tipo 1 de Angiotensina , Cloreto de Sódio/metabolismo , Cloreto de Sódio/farmacologia , Remodelação Ventricular/efeitos dos fármacosRESUMO
Mammalian sterile 20-like kinase-1 (Mst1) plays an important role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion. Whether or not Mst1 is also involved in the long-term development of heart failure after myocardial infarction (MI) is unknown. We addressed this issue using transgenic mice with cardiac specific overexpression of dominant negative Mst1 (Tg-DN-Mst1). The left coronary artery was permanently ligated, and the size of MI was similar between Tg-DN-Mst1 and nontransgenic controls (NTg). After 4 weeks, Mst1 was significantly activated in the remodeling area in NTg, but not in Tg-DN-Mst1. Although left ventricular (LV) enlargement was significantly attenuated in Tg-DN-Mst1 compared with NTg, neither LV weight/body weight nor myocyte cross sectional area was statistically different between Tg-DN-Mst1 and NTg. LV ejection fraction was significantly greater in Tg-DN-Mst1 than in NTg (53 versus 38%, P<0.01), whereas LV end-diastolic pressure (6 versus 12 mm Hg, P<0.05) and lung weight/body weight (9.8 versus 12.2 P<0.05) were significantly smaller in Tg-DN-Mst1 than in NTg. The number of TUNEL-positive myocytes (0.17 versus 0.28%, P<0.05) and amount of interstitial fibrosis (5.0 versus 7.1%, P<0.05) in the remodeling area were significantly less in Tg-DN-Mst1 than in NTg. Upregulation of matrix metalloproteinase 2 and proinflammatory cytokines was significantly attenuated in Tg-DN-Mst1. These results indicate that endogenous Mst1 plays an important role in mediating cardiac dilation, apoptosis, fibrosis, and cardiac dysfunction, but not cardiac hypertrophy, after MI. Inhibition of Mst1 improves cardiac function without attenuating cardiac hypertrophy. Thus, Mst1 may be an important target of heart failure treatment.
Assuntos
Apoptose , Cardiomegalia/etiologia , Fator de Crescimento de Hepatócito/fisiologia , Infarto do Miocárdio/complicações , Miocárdio/patologia , Proteínas Proto-Oncogênicas/fisiologia , Disfunção Ventricular Esquerda/prevenção & controle , Animais , Citocinas/fisiologia , Fibrose , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/patologia , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Remodelação VentricularRESUMO
Matrix metalloproteinases (MMPs) have been implicated in the process of neovascularization. However, the exact roles of individual MMPs in vessel formation are poorly understood. To study the putative role of MMP-2 in ischemia-induced neovascularization, a hindlimb ischemia model was applied to MMP-2(+/+) and MMP-2(-/-) mice. Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in MMP-2(-/-) young and old mice remained impaired throughout the follow-up period. At day 35, microangiography and anti-l-lectin immunohistochemical staining revealed lesser developed collateral vessels and capillary formation in both old and young MMP-2(-/-) mice compared with the age-matched MMP-2(+/+) mice. An aortic-ring culture assay showed a markedly impaired angiogenic response in MMP-2(-/-) mice, which was partially recovered by supplementation of the culture medium with recombinant MMP-2. Aorta-derived endothelial cells or bone marrow-derived endothelial progenitor cell (EPC)-like c-Kit(+) cells from MMP-2(-/-) showed marked impairment of invasive or/and proliferative abilities. At day 7, plasma and ischemic tissues of vascular endothelial growth factor protein were reduced in MMP-2(-/-). Flow cytometry showed that the numbers of EPC-like CD31(+)c-Kit(+) cells in peripheral blood markedly decreased in MMP-2-deficient mice. Transplantation of bone marrow-derived mononuclear cells from MMP-2(+/+) mice restored neovascularization in MMP-2(-/-) young mice. These data suggest that MMP-2 deficiency impairs ischemia-induced neovascularization through a reduction of endothelial cell and EPC invasive and/or proliferative activities and EPC mobilization.
Assuntos
Isquemia/fisiopatologia , Metaloproteinase 2 da Matriz/genética , Neovascularização Fisiológica/genética , Fatores Etários , Amputação Cirúrgica , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Transplante de Medula Óssea , Capilares/efeitos dos fármacos , Capilares/patologia , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Citometria de Fluxo , Membro Posterior/irrigação sanguínea , Membro Posterior/fisiopatologia , Metaloproteinase 2 da Matriz/farmacologia , Camundongos , Camundongos Knockout , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Proteínas Proto-Oncogênicas c-kit/biossíntese , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
OBJECTIVE: To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)]. METHODS: DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls. RESULTS: Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase-dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin. CONCLUSIONS: The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Animais , Ácido Azetidinocarboxílico/análogos & derivados , Ácido Azetidinocarboxílico/farmacologia , Diástole/efeitos dos fármacos , Diástole/fisiologia , Di-Hidropiridinas/farmacologia , Imidazóis/farmacologia , Masculino , Ratos , Ratos Endogâmicos Dahl , Tetrazóis/farmacologiaRESUMO
Loop diuretics could adversely influence prognosis due to activation of neurohumoral mechanism in the long term. Previous study showed torasemide, a loop diuretic with anti-aldosteronergic properties, was associated with lower mortality in patients with chronic heart failure (CHF). We evaluated the effects of torasemide, in comparison with azosemide, in patients with CHF. Patients received oral diuretic therapy with torasemide (8 mg/d, n = 15) or azosemide (60 mg/d, n = 15) for 3 months. Torasemide and azosemide were then switched, and the patients were treated for another 3 months. Torasemide treatment induced significant decreases in left ventricular (LV) systolic wall stress (from 259 +/- 95 to 232 +/- 80 kdyn/cm2) and the plasma level of aldosterone (from 133 +/- 61 to 95 +/- 50 pg/mL) and was not associated with a change in the plasma level of norepinephrine. In contrast, the plasma level of norepinephrine was significantly increased (from 370 +/- 170 to 481 +/- 247 pg/mL), whereas LV systolic wall stress was unchanged after azosemide treatment. This study indicates that torasemide treatment reduced LV systolic wall stress without activation of the sympathetic nervous system in patients with CHF. The anti-aldosteronergic properties of torasemide may contribute to its favorable effects.
Assuntos
Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Sulfanilamidas/uso terapêutico , Sulfonamidas/uso terapêutico , Sistema Nervoso Simpático/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico , Administração Oral , Aldosterona/sangue , Estudos Cross-Over , Preparações de Ação Retardada , Esquema de Medicação , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Sistema Nervoso Simpático/fisiopatologia , Sístole , Torasemida , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10-8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci-TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A-are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.