Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Am J Hum Biol ; : e23486, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32851723

RESUMO

OBJECTIVES: The origin and differentiation of Austronesian populations and their languages have long fascinated linguists, archeologists, and geneticists. However, the founding process of Austronesians and when they separated from their close relatives, such as the Daic and Austro-Asiatic populations in the mainland of Asia, remain unclear. In this study, we explored the paternal origin of Malays in Southeast Asia and the early differentiation of Austronesians. MATERIALS AND METHODS: We generated whole Y-chromosome sequences of 50 Malays and co-analyzed 200 sequences from other Austronesians and related populations. We generated a revised phylogenetic tree with time estimation. RESULTS: We identified six founding paternal lineages among the studied Malays samples. These founding lineages showed a surprisingly coincident expansion age at 5000 to 6000 years ago. We also found numerous mostly close related samples of the founding lineages of Malays among populations from Mainland of Asia. CONCLUSION: Our analyses provided a refined phylogenetic resolution for the dominant paternal lineages of Austronesians found by previous studies. We suggested that the co-expansion of numerous founding paternal lineages corresponds to the initial differentiation of the most recent common ancestor of modern Austronesians. The splitting time and divergence pattern in perspective of paternal Y-chromosome evidence are highly consistent with the previous theories of ethnologists, linguists, and archeologists.

2.
Shanghai Kou Qiang Yi Xue ; 29(2): 202-207, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32626886

RESUMO

PURPOSE: The aim of the study was to investigate the dental changes of patients with obstructive sleep apnea hypopnea syndrome (OSAHS) with long-term treatment of oral appliances, via the method of three-dimensional model analysis. METHODS: Using Geomagic Studio 2014 software, we transferred the dental models, which were from 18 OSAHS patients before and after treatment of oral appliances, into three-dimensional models for digital analysis. Datasets obtained from pre- and after treatment were compared for accuracy via paired t test using SPSS 22.0 software package. RESULTS: Eighteen patients using oral appliances for 6.57±1.98 years, showed significant differences in some dentition values between pre-treatment and after-treatment. The total dentition changes indicated intrusion of upper premolars, buccalization of upper posterior teeth and mesialization of lower posterior teeth. Statistical analysis demonstrated decrease in upper dental arch length, increase in upper posterior arch width and decrease in upper arch depth and dramatic reduction of overjet in anterior teeth. In the same time, other values evaluated showed no significant change before and after treatment of oral appliances. CONCLUSIONS: Long-term wearing oral appliances results in changes in several variables of dental occlusion, which should not be ignored for dentists conducting this treatment plan. However, the side effect of dental occlusion changes is little on a whole, leading to high security in this aspect.


Assuntos
Sobremordida , Apneia Obstrutiva do Sono , Dente Pré-Molar , Humanos , Assistência de Longa Duração
3.
Elife ; 82019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31763980

RESUMO

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.


Assuntos
Face/anatomia & histologia , Loci Gênicos/genética , Desenvolvimento Maxilofacial/genética , Fenótipo , Adolescente , Adulto , Pontos de Referência Anatômicos , Padronização Corporal/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
4.
Mol Genet Genomics ; 293(5): 1293-1300, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29923068

RESUMO

Diffusion of Tibeto-Burman populations across the Tibetan Plateau led to the largest human community in a high-altitude environment and has long been a focus of research on high-altitude adaptation, archeology, genetics, and linguistics. However, much uncertainty remains regarding the origin, diversification, and expansion of Tibeto-Burman populations. In this study, we analyzed a 7.0M bp region of 285 Y-chromosome sequences, including 81 newly reported ones, from male samples from Tibeto-Burman populations and other related Eastern Asian populations. We identified several paternal lineages specific to Tibeto-Burman populations, and most of these lineages emerged between 6000 and 2500 years ago. A phylogenetic tree and lineage dating both support the hypothesis that the establishment of Tibeto-Burman ancestral groups was triggered by Neolithic expansions from the middle Yellow River Basin and admixtures with local populations on the Tibetan Plateau who survived the Paleolithic Age. Furthermore, according to the geographical distributions of the haplogroups, we propose that there are two Neolithic expansion origins for all modern Tibeto-Burman populations. Our research provides a clear scenario about the sources, admixture process and later diffusion process of the ancestor population of all Tibeto-Burman populations.


Assuntos
Adaptação Fisiológica/genética , Altitude , Cromossomos Humanos Y/genética , Genética Populacional , Haplótipos/genética , Humanos , Linguística , Masculino , Mianmar/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Tibet/epidemiologia
5.
Eur J Hum Genet ; 26(2): 230-237, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29358612

RESUMO

The Y-chromosome haplogroup C3*-Star Cluster (revised to C2*-ST in this study) was proposed to be the Y-profile of Genghis Khan. Here, we re-examined the origin of C2*-ST and its associations with Genghis Khan and Mongol populations. We analyzed 34 Y-chromosome sequences of haplogroup C2*-ST and its most closely related lineage. We redefined this paternal lineage as C2b1a3a1-F3796 and generated a highly revised phylogenetic tree of the haplogroup, including 36 sub-lineages and 265 non-private Y-chromosome variants. We performed a comprehensive analysis and age estimation of this lineage in eastern Eurasia, including 18,210 individuals from 292 populations. We discovered that the origin of populations with high frequencies of C2*-ST can be traced to either an ancient Niru'un Mongol clan or ordinary Mongol tribes. Importantly, the age of the most recent common ancestor of C2*-ST (2576 years, 95% CI = 1975-3178) and its sub-lineages, and their expansion patterns, are consistent with the diffusion of all Mongolic-speaking populations, rather than Genghis Khan himself or his close male relatives. We concluded that haplogroup C2*-ST is one of the founder paternal lineages of all Mongolic-speaking populations, and direct evidence of an association between C2*-ST and Genghis Khan has yet to be discovered.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Y/genética , Evolução Molecular , Efeito Fundador , Haplótipos , Humanos , Masculino
6.
Mol Genet Genomics ; 293(3): 657-663, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29288348

RESUMO

The Y-chromosome haplogroup C2c1a1a1-M407 is a predominant paternal lineage in Mongolic-speaking populations, especially in Buryats and Kalmyks. However, the origin and internal phylogeny of C2c1a1a1-M407 have not been investigated in detail. In this study, we analyzed twenty-three Y-chromosome sequences of haplogroup C2c1a1a1-M407 and its most closely related clades. We generated a high-resolution phylogenetic tree of haplogroup C2c1a1a1-M407 and its upstream clade C2c1a1-CTS2657, including 32 subclades and 144 non-private Y-chromosome polymorphisms. We discover that all available C2c1a1a1-M407 samples from Mongolic-speaking populations belong to its newly defined downstream clade C2c1a1a1b-F8465, whereas all samples of C2c1a1-CTS2657(xF8465) come from northern Han Chinese, Korean, and Japanese. Furthermore, we observe that C2c1a1a1b-F8465 and its subclade C2c1a1a1b1-F8536 expanded at approximately 0.86 and 0.44 thousand years ago, respectively. Therefore, we conclude that C2c1a1a1-M407 in Mongolic-speaking populations has originated from northeastern Asia. C2c1a1a1b1-F8536, the newly defined subclade of C2c1a1a1-M407, probably represents the genetic relationships between ancient Oyrats, modern Kalmyks, Mongolians, and Buryats.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Cromossomos Humanos Y/genética , Análise de Sequência de DNA/métodos , Grupo com Ancestrais do Continente Asiático/genética , China/etnologia , Genética Populacional , Haplótipos , Humanos , Japão/etnologia , Filogenia , República da Coreia/etnologia
7.
Zool Res ; 38(3): 155-162, 2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28585439

RESUMO

Tibetans are well adapted to high-altitude hypoxia. Previous genome-wide scans have reported many candidate genes for this adaptation, but only a few have been studied. Here we report on a hypoxia gene ( GCH1, GTP-cyclohydrolase I), involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure, that harbors many potentially adaptive variants in Tibetans. We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans. Combined with previously published data, we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese. Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans. Moreover, association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans, including blood nitric oxide concentration, blood oxygen saturation, and hemoglobin concentration. Taken together, we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia.


Assuntos
Adaptação Fisiológica , Altitude , Grupos Étnicos , GTP Cicloidrolase/metabolismo , Regulação Enzimológica da Expressão Gênica/genética , Adulto , Sequência de Bases , Feminino , GTP Cicloidrolase/genética , Variação Genética , Humanos , Masculino , Tibet
8.
Zool Res ; 38(3): 163-170, 2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28585440

RESUMO

The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene EP300 (histone acetyltransferase p300), we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans. The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans, with a group of variants showing allelic divergence between Tibetans and lowland reference populations, including Han Chinese, Europeans, and Africans. Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation. More importantly, genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide (NO) concentration. Collectively, we propose that EP300 harbors adaptive variants in Tibetans, which might contribute to high-altitude adaptation through regulating NO production.


Assuntos
Adaptação Fisiológica , Altitude , Proteína p300 Associada a E1A/metabolismo , Grupos Étnicos , Óxido Nítrico/metabolismo , Adulto , Sequência de Bases , Proteína p300 Associada a E1A/genética , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Tibet
9.
PLoS One ; 12(4): e0175080, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28380021

RESUMO

Austronesian diffusion is considered one of the greatest dispersals in human history; it led to the peopling of an extremely vast region, ranging from Madagascar in the Indian Ocean to Easter Island in Remote Oceania. The Y-chromosome haplogroup O3a2b*-P164(xM134), a predominant paternal lineage of Austronesian populations, is found at high frequencies in Polynesian populations. However, the internal phylogeny of this haplogroup remains poorly investigated. In this study, we analyzed -seventeen Y-chromosome sequences of haplogroup O3a2b*-P164(xM134) and generated a revised phylogenetic tree of this lineage based on 310 non-private Y-chromosome polymorphisms. We discovered that all available O3a2b*-P164(xM134) samples belong to the newly defined haplogroup O3a2b2-N6 and samples from Austronesian populations belong to the sublineage O3a2b2a2-F706. Additionally, we genotyped a series of Y-chromosome polymorphisms in a large collection of samples from China. We confirmed that the sublineage O3a2b2a2b-B451 is unique to Austronesian populations. We found that O3a2b2-N6 samples are widely distributed on the eastern coastal regions of Asia, from Korea to Vietnam. Furthermore, we propose- that the O3a2b2a2b-B451 lineage represents a genetic connection between ancestors of Austronesian populations and ancient populations in North China, where foxtail millet was domesticated about 11,000 years ago. The large number of newly defined Y-chromosome polymorphisms and the revised phylogenetic tree of O3a2b2-N6 will be helpful to explore the origin of proto-Austronesians and the early diffusion process of Austronesian populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Y/genética , Grupo com Ancestrais Oceânicos/genética , China , Técnicas de Genotipagem , Haplótipos/genética , História Antiga , Migração Humana/história , Humanos , Coreia (Geográfico) , Masculino , Filogeografia , Polimorfismo Genético/genética , Vietnã
10.
Yi Chuan ; 38(6): 543-559, 2016 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-27655316

RESUMO

Over the last decade, a larger number of type 2 diabetes mellitus (T2DM) susceptible candidate genes have been reported by numerous genome-wide association studies (GWAS). Understanding the genetic diversity of these candidate genes among worldwide populations not only facilitates to elucidating the genetic mechanism of T2DM, but also provides guidance to further studies of pathogenesis of T2DM in any certain population. In this study, we identified 170 genes or genomic regions associated with T2DM by searching the GWAS databases and related literatures. We next analyzed the genetic diversity of these genes (or genomic regions) among present-day human populations by curetting the 1000 Genomes Projects phase1 dataset covering 14 worldwide populations. We further compared the characteristics of T2DM genes in different populations. No significant differences of genetic diversity were observed among the 14 worldwide populations between the T2DM candidate genes and the non-T2DM genes in terms of overall pattern. However, we observed some genes, such as IL20RA, RNMTL1-NXN, NOTCH2, ADRA2A-BTBD7P2, TBC1D4, RBM38-HMGB1P1, UBE2E2, and PPARD, show considerable differentiation between populations. In particular, IL20RA (FST=0.1521) displays the greatest population difference which is mainly contributed by that between Africans and non-Africans. Moreover, we revealed genetic differences between East Asians and Europeans on some candidate genes such as DGKB-AGMO (FST=0.173) and JAZF1 (FST=0.182). Our results indicate that some T2DM susceptible candidate genes harbor highly-differentiated variants between populations. These analyses, despite preliminary, should advance our understanding of the population difference of susceptibility to T2DM and provide insightful reference that future studies can relay on.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , África , Grupo com Ancestrais do Continente Asiático/genética , Europa (Continente) , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos
11.
Sci Rep ; 5: 14139, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26420475

RESUMO

Of the two cultivated species of allopolyploid cotton, Gossypium barbadense produces extra-long fibers for the production of superior textiles. We sequenced its genome (AD)2 and performed a comparative analysis. We identified three bursts of retrotransposons from 20 million years ago (Mya) and a genome-wide uneven pseudogenization peak at 11-20 Mya, which likely contributed to genomic divergences. Among the 2,483 genes preferentially expressed in fiber, a cell elongation regulator, PRE1, is strikingly At biased and fiber specific, echoing the A-genome origin of spinnable fiber. The expansion of the PRE members implies a genetic factor that underlies fiber elongation. Mature cotton fiber consists of nearly pure cellulose. G. barbadense and G. hirsutum contain 29 and 30 cellulose synthase (CesA) genes, respectively; whereas most of these genes (>25) are expressed in fiber, genes for secondary cell wall biosynthesis exhibited a delayed and higher degree of up-regulation in G. barbadense compared with G. hirsutum, conferring an extended elongation stage and highly active secondary wall deposition during extra-long fiber development. The rapid diversification of sesquiterpene synthase genes in the gossypol pathway exemplifies the chemical diversity of lineage-specific secondary metabolites. The G. barbadense genome advances our understanding of allopolyploidy, which will help improve cotton fiber quality.


Assuntos
Evolução Biológica , Fibra de Algodão , Genoma de Planta , Genômica , Gossypium/genética , Gossypium/metabolismo , Metabolômica , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Cromossomos de Plantas , Análise por Conglomerados , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Estudos de Associação Genética , Genômica/métodos , Metabolômica/métodos , Anotação de Sequência Molecular , Fenótipo , Filogenia , Poliploidia , Característica Quantitativa Herdável , Sesquiterpenos/metabolismo , Translocação Genética
12.
J Dig Dis ; 14(4): 196-202, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23241512

RESUMO

OBJECTIVES: To identify gene polymorphisms that differ between Malays, Han Chinese and South Indians, and to identify candidate genes for the investigation of their role in protecting Malays from Helicobacter pylori (H. pylori) infection. METHODS: Malay participants born and residing in Kelantan with a documented absence of H. pylori infection were studied. Venous blood was used for genotyping using the Affymetrix 50K Xba I kit. CEL files from 141 Han Chinese and 76 South Indians were analyzed to compare their allele frequency with that of the Malays using fixation index (FST ) calculation. The single nucleotide polymorphisms (SNPs) with the highest allele frequency (outliers) were then examined for their functional characteristics using F-SNP software and the Entrez Gene database. RESULTS: In all, 37 Malays were enrolled in the study; of whom 7 were excluded for low genotyping call rates. The average FST estimated from the genome-wide data were 0.038 (Malays in Kelantan vs the South Indians), 0.015 (Malays in Kelantan vs Han Chinese) and 0.066 (Han Chinese vs South Indians), respectively. The outlier gene variants present in Malays with functional characteristics were C7orf10 (FST 0.29988), TSTD2 (FST 0.43278), SMG7 (FST 0.29877) and XPA (FST 0.43393 and 0.43644). CONCLUSION: Genetic variants possibly related to protection against H. pylori infection in ethnic Malays from the north-eastern region of Peninsular Malaysia were identified for testing in subsequent trials among infected and uninfected Malays.


Assuntos
Infecções por Helicobacter/etnologia , Infecções por Helicobacter/genética , Helicobacter pylori/isolamento & purificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , China/etnologia , Resistência à Doença/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Índia/etnologia , Malásia/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prevalência , Adulto Jovem
13.
Am J Physiol Heart Circ Physiol ; 302(2): H479-88, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22037194

RESUMO

The cardiovascular effects of cyclooxygenase (COX) inhibition remain controversial, especially in the setting of cardiovascular comorbidities. We examined the effects of nonselective and selective COX inhibition on cardiovascular function in a hypercholesterolemic swine model of chronic ischemia. Twenty-four intact male Yorkshire swine underwent left circumflex ameroid constrictor placement and were subsequently given either no drug (HCC; n = 8), a nonselective COX inhibitor (440 mg/day naproxen; HCNS; n = 8), or a selective COX-2 inhibitor (200 mg/day celecoxib; HCCX; n = 8). After 7 wk, myocardial functional was measured and myocardium from the nonischemic ventricle and ischemic area-at-risk (AAR) were analyzed. Regional function as measured by segmental shortening was improved in the AAR of HCCX compared with HCC. There was no significant difference in perfusion to the nonischemic ventricle between groups, but myocardial perfusion in the AAR was significantly improved in the HCCX group compared with controls at rest and during pacing. Endothelium-dependent microvessel relaxation was diminished by ischemia in HCC animals, but both naproxen and celecoxib improved vessel relaxation in the AAR compared with controls, and also decreased the vasoconstrictive response to serotonin. Thromboxane levels in the AAR were decreased in both HCNS and HCCX compared with HCC, whereas prostacyclin levels were decreased only in HCNS, corresponding to a decrease in prostacyclin synthase expression. Chronic ischemia increased apoptosis in Troponin T negative cells and intramyocardial fibrosis, both of which were reduced by celecoxib administration in the AAR. Capillary density was decreased in both the HCNS and HCCX groups. Protein oxidative stress was decreased in both HCNS and HCCX, whereas lipid oxidative stress was decreased only in the HCCX group. Thus nonselective and especially selective COX inhibition may have beneficial myocardial effects in the setting of hypercholesterolemia and chronic ischemia. Whether these effects modulate cardiovascular risk in patients taking these drugs remains to be seen, but evidence to date suggests that they do not.


Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Coração/efeitos dos fármacos , Hipercolesterolemia/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Miocárdio/metabolismo , Naproxeno/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Celecoxib , Inibidores de Ciclo-Oxigenase/farmacologia , Coração/fisiopatologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/fisiopatologia , Masculino , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Naproxeno/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Suínos
14.
Surgery ; 150(3): 490-6, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21878235

RESUMO

BACKGROUND: The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the cardiovascular system remains controversial, especially in patients with cardiovascular comorbidities. We used a swine model of chronic myocardial ischemia to investigate whether hypercholesterolemia alters the cardiovascular effects of the nonselective NSAID naproxen. METHODS: Yorkshire swine were fed normal chow (NAP; n = 7) or a high-fat diet (HF-NAP; n = 8). Chronic myocardial ischemia was created in all animals by left circumflex ameroid constrictor placement. All swine were started on oral naproxen (440 mg/day) at the time of ameroid placement. After 7 weeks, myocardial perfusion and microvessel reactivity in the ischemic territory were assessed. Tissue levels of prostanoid metabolites 11-dehydrothromboxane B2 (11-d-TXB2) and 6-keto-prostaglandin F1-α (6-k-PGF(1α)) were measured. Tissue was analyzed for capillary density and protein expression. RESULTS: Myocardial perfusion was significantly decreased in the HF-NAP group both at rest and during ventricular pacing. Microvessel relaxation responses to sodium nitroprusside and adenosine 5'-diphosphate were similar between groups. Tissue 11-d-TXB2 levels were similar between groups, but tissue 6-k-PGF(1α) was significantly decreased in the HF-NAP group (P = .001). Expression of thromboxane synthase was significantly higher in the HF-NAP group (P = .02), while prostacyclin synthase expression was significantly decreased in the HF-NAP group (P = .04). Capillary density was higher in the HF-NAP group (P = .005). Proangiogenic vascular endothelial growth factor (VEGF; P = .0002) and Akt (P = .01) were downregulated in the HF-NAP group. CONCLUSION: A high-fat diet impairs tissue perfusion in ischemic myocardium of naproxen-treated swine by shifting the prostanoid balance to favor production of thromboxane over prostacyclin. Dietary modification may improve myocardial blood flow and alter the safety profile in chronically ischemic cardiac patients taking naproxen.


Assuntos
Gorduras na Dieta/farmacologia , Hipercolesterolemia/fisiopatologia , Isquemia Miocárdica/tratamento farmacológico , Naproxeno/administração & dosagem , Prostaglandinas/metabolismo , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Circulação Coronária/fisiologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Testes de Função Cardíaca , Hipercolesterolemia/tratamento farmacológico , Immunoblotting , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Perfusão , Prostaglandinas/sangue , Distribuição Aleatória , Valores de Referência , Sensibilidade e Especificidade , Suínos , Fator A de Crescimento do Endotélio Vascular/sangue
15.
J Mol Cell Cardiol ; 49(6): 1022-30, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20826160

RESUMO

We investigated the role of neuropeptide Y (NPY), abundant in the myocardial sympathetic nervous system and endothelial cells, in angiogenesis during chronic myocardial ischemia. Adult male Yorkshire swine underwent ameroid constrictor placement on the proximal left circumflex coronary artery. After 3 weeks, an osmotic pump was placed to deliver either placebo (control, n=8) or NPY(3-36) (NPY, n=8) to the collateral dependent region. Five weeks after pump placement, after cardiac catheterization and hemodynamic assessment, the heart was harvested for analysis. NPY treated animals demonstrated increased mean arterial pressures and improved left ventricular function (+dP/dt). Cardiac catheterization demonstrated a significant increase in the blush score in the NPY group (p<0.001). Blood flow to the ischemic myocardium was not different between groups at rest or during ventricular pacing. Immunohistochemical double staining for CD-31 and smooth muscle actin demonstrated an increase in capillary and arteriole formation in NPY treated animals (p=0.02 and p<0.001). Immunoblotting showed a significant upregulation of DPPIV (p=0.009) and NPY receptors 1 (p=0.008), 2 (p=0.02) and 5 (p=0.03) in the NPY treated group. Additionally, there was significant upregulation of VEGF (p=0.04), eNOS (p=0.014), phospho-eNOS (ser1177) (p=0.02), and PDGF (p<0.001) in NPY treated group. The anti-angiogenic factors endostatin and angiostatin were significantly decreased in NPY treated animals (endostatin, p=0.03; angiostatin, p=0.04). Exogenous NPY(3-36) resulted in improved myocardial function and increased angiogenesis and arteriogenesis by stimulating growth factor, pro-angiogenic receptor upregulation, and decreasing anti-angiogenic expression, but did not increase blood flow to the ischemic myocardium. NPY may act as a good adjunct to primary agents of therapeutic angiogenesis.


Assuntos
Circulação Colateral/efeitos dos fármacos , Isquemia Miocárdica/fisiopatologia , Neuropeptídeo Y/farmacologia , Animais , Doença Crônica , Angiografia Coronária , Modelos Animais de Doenças , Testes de Função Cardíaca , Immunoblotting , Imuno-Histoquímica , Microvasos/efeitos dos fármacos , Microvasos/patologia , Microvasos/fisiopatologia , Modelos Biológicos , Isquemia Miocárdica/diagnóstico por imagem , Perfusão , Sus scrofa
16.
Ann Thorac Surg ; 87(3): 786-93, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19231390

RESUMO

BACKGROUND: Myocardial ischemia-reperfusion injury may lead to cardiac dysfunction or death. This study investigates the potential efficacy of a novel thrombin fragment (TP508) on myocardial ischemia-reperfusion injury. METHODS: Fourteen male Yucatan pigs underwent 60 minutes of mid-left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. Pigs received either saline vehicle (control, n = 7) or thrombin fragment TP508 (n = 7) as a bolus (0.5 mg/kg) 50 minutes into the ischemic period, followed by continuous intravenous infusion (1.25 mg x kg(-1) x h(-1)) during reperfusion. Myocardial function was monitored throughout the experiments. Monastryl blue/triphenyl tetrazolium chloride staining was utilized to measure the area at risk and infarcted tissue. Apoptosis was assessed by Western blotting and dUTP nick-end labeling (TUNEL) staining. Coronary microvascular reactivity to endothelium-dependent factors (adenosine diphosphate, substance P, A23187) and endothelium-independent factor (sodium nitroprusside) was examined. RESULTS: Global and regional left ventricular function was not significantly different between groups. Endothelium-dependent coronary microvascular relaxation was greater in the TP508 group and associated with higher endothelial nitric oxide synthase phosphorylation. Both infarct size and TUNEL staining was significantly decreased in the TP508 group compared with the control group (p < 0.05). Expression of the cell survival proteins B-cell lymphoma 2 (2.2-fold, p < 0.05) and heat shock protein-73 (1.6-fold, p < 0.05) was higher in the TP508 group. Expression of the cell-death-signaling proteins poly adenosine diphosphate-ribose polymerase (1.6-fold, p < 0.05), cleaved poly adenosine diphosphate-ribose polymerase (6.4-fold, p < 0.05), and B-cell lymphoma 2/adenovirus E1B 19 kDa-interacting protein 3 (3.8-fold, p < 0.05) was significantly higher in the TP508 group in the ischemic territory. CONCLUSIONS: This study demonstrates that TP508 decreases infarct size, improves endothelial microvascular function, and induces cell-survival signaling in the setting of ischemia-reperfusion injury. Thus, TP508 may be a useful agent to attenuate myocardial reperfusion injury.


Assuntos
Apoptose/efeitos dos fármacos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/complicações , Fragmentos de Peptídeos/uso terapêutico , Animais , Masculino , Fragmentos de Peptídeos/farmacologia , Suínos , Trombina
17.
Am J Physiol Heart Circ Physiol ; 296(2): H428-34, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19074676

RESUMO

Coronary artery disease (CAD) is the leading cause of mortality in diabetic patients. Because of the diffuse nature of their disease, diabetic patients may be at risk for incomplete revascularization, highlighting a potential role for proangiogenic therapy in this group. This study investigates molecular mechanisms of angiogenesis in diabetic patients. Myocardial tissue was harvested from patients undergoing coronary artery bypass grafting [nondiabetic (ND) 11, type 2 diabetic (DM) 10]. Expression of angiostatin, endostatin, their precursors (plasminogen and collagen XVIII, respectively), enzymes leading to their production [matrix metalloprotease (MMP)-2 and -9, cathepsin L], and an inhibitor of MMPs (tissue inhibitor of metalloproteinase) was assessed with Western blotting. MMP activity was assessed. Coronary collateralization was graded by Rentrop scoring of angiograms. Plasminogen and collagen XVIII expression were similar between groups. Angiostatin expression trended to increase 1.24-fold (P = 0.07), and endostatin expression increased 2.02-fold in DM patients relative to ND (P = 0.02). MMP-9 expression was no different between groups, whereas MMP-2 expression decreased 1.8-fold in diabetics (P = 0.003). MMP-2 and -9 activity decreased 1.33-fold (P = 0.03) and 1.57-fold (P = 0.04), respectively, in diabetic patients. Cathepsin L expression was 1.38-fold higher in diabetic patients (P = 0.02). Coronary collateralization scores were ND 2.1 +/- 0.37 vs. DM 1.0 +/- 0.4 (P = 0.05). Myocardial endostatin expression correlated strongly with the percentage of hemoglobin A(1c) (r = 0.742, P = 0.0001). Myocardial expression of angiostatin and endostatin demonstrated significant negative linear correlations with coronary collateralization (angiostatin r = -0.531, P = 0.035, endostatin r = -0.794, P = 0.0002). Diabetic patients with CAD exhibit increased levels of the antiangiogenic proteins angiostatin and endostatin and differential regulation of the enzymes governing their production relative to ND patients. Myocardial levels of these proteins show significant correlation to coronary collateralization. These findings offer potential new therapeutic targets for enhancing proangiogenic therapy and insight into the angiogenic impairments seen in diabetes.


Assuntos
Angiostatinas/análise , Circulação Colateral , Doença da Artéria Coronariana/metabolismo , Circulação Coronária , Complicações do Diabetes/metabolismo , Endostatinas/análise , Miocárdio/química , Idoso , Catepsina L , Catepsinas/análise , Colágeno Tipo XVIII/análise , Ponte de Artéria Coronária , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/cirurgia , Cisteína Endopeptidases/análise , Complicações do Diabetes/fisiopatologia , Complicações do Diabetes/cirurgia , Feminino , Hemoglobina A Glicada/análise , Humanos , Modelos Lineares , Masculino , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Miocárdio/enzimologia , Plasminogênio/análise , Inibidor Tecidual de Metaloproteinase-2/análise
18.
J Card Surg ; 23(4): 312-20, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18598320

RESUMO

BACKGROUND/AIM: Atorvastatin has previously been shown to reduce the endogenous angiogenic response to chronic ischemia in a porcine model. One possible mechanism for this effect is reduced bioavailability of nitric oxide, a key mediator of angiogenesis, secondary to increased oxygen free radicals. We sought to determine if atorvastatin modulates oxidative stress in myocardial tissue. METHODS: Dietary induction of hypercholesterolemia was performed over 20 weeks in Yucatan swine with treated animals receiving atorvastatin 3 mg/kg/day. Chronic myocardial ischemia was induced via surgical placement of an ameroid constrictor ring around the proximal circumflex artery at age 20 weeks, followed by tissue harvest at age 27 weeks. Myocardial levels of protein, lipid, and DNA biomarkers of oxidative stress, serum levels of 8-isoprostane, nitric oxide (NO) dependent, and independent coronary microvascular reactivity, as well as isotope-labeled microsphere myocardial perfusion analysis and histologic analysis for endothelial cell density was performed. RESULTS: Atorvastatin treatment was associated with elevated levels of myocardial protein oxidation and lipid peroxidation. Conversely, serum oxidant stress biomarkers were not elevated. Atorvastatin treatment improved nitric oxide dependent and independent microvascular reactivity, and was associated with decreased perfusion in the ischemic myocardial territory. CONCLUSION: Treatment with atorvastatin was associated with increased levels of myocardial tissue protein and lipid oxidative stress biomarkers and a reduced functional endogenous angiogenic response, but improved coronary microvascular reactivity. Increased oxidative stress in tissues may play a role in the reduced angiogenic response seen with atorvastatin treatment in other studies.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Isquemia Miocárdica/complicações , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pirróis/uso terapêutico , Difosfato de Adenosina/farmacologia , Animais , Atorvastatina , Colesterol/sangue , Circulação Coronária , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , DNA/metabolismo , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Dinoprosta/farmacologia , Endotélio Vascular/patologia , Feminino , Hipercolesterolemia/complicações , Hipercolesterolemia/metabolismo , Técnicas In Vitro , Peroxidação de Lipídeos , Masculino , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Oxirredução , Proteínas/metabolismo , Suínos , Porco Miniatura , Vasodilatação/efeitos dos fármacos
19.
Arch Surg ; 143(5): 463-70, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18490555

RESUMO

HYPOTHESIS: Antiangiogenic protein expression is increased in skeletal muscle in the setting of diabetes. DESIGN, SETTING, AND PARTICIPANTS: In animal studies, diabetes was induced in 8 Yucatan miniswine via single alloxan injection at age 8 months, followed by skeletal muscle harvest 15 weeks later. Eight nondiabetic Yucatan miniswine served as controls. In patient studies, skeletal muscle was harvested from 11 nondiabetic patients and 10 patients with type 2 diabetes mellitus undergoing initial elective coronary artery bypass graft surgery. Skeletal muscle samples were analyzed via Western blotting and zymography for protein expression and enzyme activity. The study was performed in an academic medical center. MAIN OUTCOME MEASURES: Skeletal muscle expression of plasminogen, collagen XVIII, angiostatin, endostatin, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 2. RESULTS: Skeletal muscle expression of plasminogen and collagen XVIII (precursors of angiostatin and endostatin, respectively) remained similar between nondiabetic and diabetic swine and patients. Expression of angiostatin and endostatin was increased 1.70-fold and 1.84-fold, respectively, in diabetic swine relative to control swine. Endostatin expression was increased 1.69-fold in diabetic patients relative to nondiabetic patients. Matrix metalloproteinase 2 expression and activity were significantly increased in the skeletal muscle of diabetic swine and patients. CONCLUSIONS: Antiangiogenic protein levels are increased in the skeletal muscle in the setting of diabetes. Angiostatin, endostatin, and matrix metalloproteinases may offer novel therapeutic targets to improve collateral formation in patients with diabetes.


Assuntos
Angiostatinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endostatinas/metabolismo , Músculo Esquelético/metabolismo , Idoso , Animais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Suínos , Porco Miniatura
20.
J Thorac Cardiovasc Surg ; 135(1): 117-22, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18179927

RESUMO

OBJECTIVE: Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, used routinely in patients with coronary disease, can improve endothelial function but can have biphasic and dose-dependent effects on angiogenesis. In vitro evidence suggests that the proangiogenic effects of statins are linked to activation of Akt, a mediator of endothelial cell survival and an activator of endothelial nitric oxide synthase. We investigated the functional and molecular effects of atorvastatin supplementation on microvascular function and the endogenous angiogenic response to chronic myocardial ischemia in normocholesterolemic swine. METHODS: Yucatan miniswine were fed a normal diet with (ATOR, n = 7) or without (control, n = 8) atorvastatin (1.5 mg/kg/d) for 20 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Myocardial perfusion was assessed at 3 and 7 weeks using isotope-labeled microspheres. In vitro microvessel relaxation responses and myocardial protein expression were evaluated. RESULTS: Endothelium-dependent relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were intact in both groups. The ATOR group demonstrated impaired microvessel relaxation to vascular endothelial growth factor (53% +/- 3% vs 70% +/- 7%, ATOR vs NORM at 10(-10) mol/L, P = .05) and fibroblast growth factor-2 (35% +/- 3% vs 57% +/- 5%, ATOR vs NORM at 10(-10) mol/L, P = .04). Baseline-adjusted myocardial perfusion in the ischemic circumflex territory was significantly reduced in the ATOR group (-0.29 +/- 0.10 mL/min/g vs NORM, P = .009). Phosphorylation of Akt was significantly increased in the ATOR group (+235% +/- 72%, P = .009 vs NORM), as was the myocardial expression of endostatin, an antiangiogenic protein (+51% +/- 9%, P < .001 vs NORM). Expression of vascular endothelial growth factor, Tie-2, fibroblast growth factor receptor-1, and endothelial nitric oxide synthase was similar in both groups. CONCLUSIONS: Atorvastatin supplementation is associated with impaired growth factor-mediated microvessel relaxation and a significant reduction in collateral-dependent perfusion. Chronic Akt activation, increased myocardial expression of endostatin, and impaired growth factor signaling may account for the diminished endogenous angiogenic response observed with atorvastatin treatment.


Assuntos
Circulação Coronária/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Isquemia Miocárdica/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Pirróis/farmacologia , Animais , Atorvastatina , Colesterol/sangue , Circulação Colateral/efeitos dos fármacos , Feminino , Técnicas In Vitro , Masculino , Microcirculação/efeitos dos fármacos , Suínos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA