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1.
Nature ; 612(7940): 495-502, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36450981

RESUMO

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.


Assuntos
Reparo do DNA , Anemia de Fanconi , Genômica , Neoplasias de Cabeça e Pescoço , Humanos , Aldeídos/efeitos adversos , Aldeídos/metabolismo , Reparo do DNA/genética , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Neoplasias de Cabeça e Pescoço/induzido quimicamente , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Infecções por Papillomavirus , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Dano ao DNA/efeitos dos fármacos
2.
Clin Genet ; 101(2): 161-182, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34355387

RESUMO

Li-Fraumeni syndrome (LFS), a rare cancer predisposition syndrome caused by germline mutations in the TP53 gene, is associated with significant lifetime risk of developing cancer and warrants extensive and long-term surveillance. There are psychosocial impacts on individuals and families living with this condition, from the initial diagnosis throughout multiple stages across the lifespan, but these impacts have not been systematically reviewed and organized. The objective of this scoping review was to synthesize and characterize the literature on psychosocial screening and outcomes, educational needs, support services, and available interventions for patients and families with LFS. A systematic search of six databases was most recently conducted in August 2020: (PubMed/MEDLINE (NLM), EMBASE (Elsevier), Cochrane Library (Wiley), CINAHL (EBSCO), PsycINFO (OVID), and Web of Science (Clarivate Analytics). A total of 15 757 titles were screened, and 24 articles included. Several important themes were identified across studies: factors associated with TP53 genetic testing, LFS surveillance, psychological outcomes, and communication. Findings related to these themes were organized into age-specific categories (age agnostic/across the lifespan, childhood, adolescence and young adulthood, and adulthood).


Assuntos
Cuidadores/psicologia , Necessidades e Demandas de Serviços de Saúde , Síndrome de Li-Fraumeni/psicologia , Intervenção Psicossocial , Fatores Etários , Gerenciamento Clínico , Genes p53 , Predisposição Genética para Doença , Testes Genéticos , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/etiologia , Síndrome de Li-Fraumeni/terapia , Intervenção Psicossocial/métodos , Vigilância em Saúde Pública , Apoio Social
3.
Artigo em Inglês | MEDLINE | ID: mdl-34250384

RESUMO

NTHL1 and MSH3 have been implicated as autosomal recessive cancer predisposition genes. Although individuals with biallelic NTHL1 and MSH3 pathogenic variants (PVs) have increased cancer and polyposis risk, risks for monoallelic carriers are uncertain. We sought to assess the prevalence and characterize NTHL1 and MSH3 from a large pan-cancer patient population. MATERIALS AND METHODS: Patients with pan-cancer (n = 11,081) underwent matched tumor-normal sequencing with consent for germline analysis. Medical records and tumors were reviewed and analyzed. Prevalence of PVs was compared with reference controls (Genome Aggregation Database). RESULTS: NTHL1-PVs were identified in 40 patients including 39 monoallelic carriers (39/11,081 = 0.35%) and one with biallelic variants (1/11,081 = 0.009%) and a diagnosis of isolated early-onset breast cancer. NTHL1-associated mutational signature 30 was identified in the tumors of the biallelic patient and two carriers. Colonic polyposis was not identified in any NTHL1 patient. MSH3-PVs were identified in 13 patients, including 12 monoallelic carriers (12/11,081 = 0.11%) and one with biallelic MSH3 variants (1/11,081 = 0.009%) and diagnoses of later-onset cancers, attenuated polyposis, and abnormal MSH3-protein expression. Of the 12 MSH3 carriers, two had early-onset cancer diagnoses with tumor loss of heterozygosity of the wild-type MSH3 allele. Ancestry-specific burden tests demonstrated that NTHL1 and MSH3 prevalence was not significantly different in this pan-cancer population versus controls. CONCLUSION: NTHL1 and MSH3 germline alterations were not enriched in this pan-cancer patient population. However, tumor-specific findings, such as mutational signature 30 and loss of heterozygosity of the wild-type allele, suggest the potential contribution of monoallelic variants to tumorigenesis in a subset of patients.


Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Heterozigoto , Proteína 3 Homóloga a MutS/genética , Adolescente , Adulto , Idoso , Alelos , Criança , Pré-Escolar , Feminino , Variação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Nat Cancer ; 2: 357-365, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-34308366

RESUMO

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias , Criança , Predisposição Genética para Doença , Células Germinativas , Mutação em Linhagem Germinativa/genética , Humanos , Neoplasias/diagnóstico , Estudos Prospectivos
5.
Artigo em Inglês | MEDLINE | ID: mdl-33172906

RESUMO

Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand cross-links. This rare disorder is characterized by congenital defects, bone marrow failure, and cancer predisposition. FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels and point and splicing variants. Genotype-phenotype associations in FA are complex, and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear. In this study, we describe two siblings with compound heterozygous FANCA variants (c.3788_3790delTCT and c.4199G > A) who both presented with esophageal squamous cell carcinoma at the age of 51. The proband came to medical attention when he developed pancytopenia after a single cycle of low-dose chemotherapy including platinum-based therapy. Other than a minor thumb abnormality, neither patient had prior findings to suggest FA, including normal blood counts and intact fertility. Patient fibroblasts from both siblings display increased chromosomal breakage and hypersensitivity to interstrand cross-linking agents as seen in typical FA. Based on our functional data demonstrating that the c.4199G > A/p.R1400H variant represents a hypomorphic FANCA allele, we conclude that the residual activity of the Fanconi anemia repair pathway accounts for lack of spontaneous bone marrow failure or infertility with the late presentation of malignancy as the initial disease manifestation. This and similar cases of adult-onset esophageal cancer stress the need for chromosome breakage testing in patients with early onset of aerodigestive tract squamous cell carcinomas before platinum-based therapy is initiated.


Assuntos
Neoplasias Esofágicas/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Sistemas CRISPR-Cas , Quebra Cromossômica , DNA , Reparo do DNA , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/terapia , Fibroblastos/metabolismo , Edição de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
6.
Cancer ; 126(13): 3114-3121, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320050

RESUMO

BACKGROUND: Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. METHODS: Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). RESULTS: Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. CONCLUSIONS: Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.


Assuntos
Síndrome de Beckwith-Wiedemann/sangue , Metilação de DNA/genética , Impressão Genômica/genética , Hepatoblastoma/sangue , Tumor de Wilms/sangue , Adolescente , Adulto , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 11/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Hepatoblastoma/genética , Hepatoblastoma/patologia , Humanos , Lactente , Masculino , Proteínas de Neoplasias/genética , Tumor de Wilms/genética , Tumor de Wilms/patologia , Adulto Jovem
7.
Proc Natl Acad Sci U S A ; 114(12): E2285-E2292, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28265075

RESUMO

The sensitivity of agricultural productivity to climate has not been sufficiently quantified. The total factor productivity (TFP) of the US agricultural economy has grown continuously for over half a century, with most of the growth typically attributed to technical change. Many studies have examined the effects of local climate on partial productivity measures such as crop yields and economic returns, but these measures cannot account for national-level impacts. Quantifying the relationships between TFP and climate is critical to understanding whether current US agricultural productivity growth will continue into the future. We analyze correlations between regional climate variations and national TFP changes, identify key climate indices, and build a multivariate regression model predicting the growth of agricultural TFP based on a physical understanding of its historical relationship with climate. We show that temperature and precipitation in distinct agricultural regions and seasons explain ∼70% of variations in TFP growth during 1981-2010. To date, the aggregate effects of these regional climate trends on TFP have been outweighed by improvements in technology. Should these relationships continue, however, the projected climate changes could cause TFP to drop by an average 2.84 to 4.34% per year under medium to high emissions scenarios. As a result, TFP could fall to pre-1980 levels by 2050 even when accounting for present rates of innovation. Our analysis provides an empirical foundation for integrated assessment by linking regional climate effects to national economic outcomes, offering a more objective resource for policy making.


Assuntos
Produtos Agrícolas/crescimento & desenvolvimento , Agricultura , Mudança Climática , Produção Agrícola , Ecossistema , Modelos Teóricos , Temperatura
8.
J Pediatr Hematol Oncol ; 39(8): e443-e445, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28060130

RESUMO

A 16-year-old male was diagnosed with Ewing sarcoma of the ribcage with pulmonary metastases. Six months after completion of scheduled therapy, he was found to have a new intracardiac mass, presumed recurrent Ewing sarcoma. EWSR1 fusion was not detected by droplet digital polymerase chain reaction from blood plasma. After no improvement with salvage chemotherapy, he underwent surgical resection that identified a low-grade spindle cell sarcoma. Despite the near-synchronous presentation of 2 unrelated sarcomas, extensive genomic analyses did not reveal any unifying somatic or germline mutations nor any apparent cancer predisposition. This case also highlights the potential role of utilizing plasma cell-free DNA for diagnosing tumors in locations where biopsy confers high morbidity.


Assuntos
Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/etiologia , Segunda Neoplasia Primária , Sarcoma de Ewing/complicações , Sarcoma/diagnóstico , Sarcoma/etiologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Proteínas de Ligação a Calmodulina/genética , Humanos , Masculino , Mutação , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma de Ewing/terapia , Tomografia Computadorizada por Raios X
9.
Cell Rep ; 12(1): 35-41, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26119737

RESUMO

Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT.


Assuntos
Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação L da Anemia de Fanconi/metabolismo , Anemia de Fanconi/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação L da Anemia de Fanconi/genética , Fibroblastos/metabolismo , Deleção de Genes , Células HEK293 , Humanos , Ligação Proteica , Enzimas de Conjugação de Ubiquitina/deficiência , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitinação
10.
J Heart Valve Dis ; 22(5): 621-30, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24383372

RESUMO

BACKGROUND AND AIM OF THE STUDY: Aortic valve stenosis is a major cause of valve replacement, particularly in the elderly. TGF-beta1 is upregulated in stenotic valves and induces calcification and collagen synthesis in cultured valve interstitial cells. It has been shown previously that TGF-beta1 increases reactive oxygen species (ROS) in these cells in association with calcifying nodule formation, but the cellular signaling pathways responsible for these TGF-beta1-induced effects are not well defined. METHODS: Cultured porcine aortic valve interstitial cells were used to investigate the effects of inhibitors of TGF-beta1 signaling pathways on 3H-proline incorporation into the extracellular matrix, the peak number of calcifying nodules formed, redox stress as dichlorofluorescein diacetate (DCF-DA) fluorescence, and senescence-associated beta-galactosidase staining. RESULTS: Nodule formation and proline incorporation were inhibited by SB431542, implicating the Smad pathway, by SB203580, implicating the P38 MAPK pathway, and by U0126, implicating the Mekl/2/Erk1/2 pathway in both processes. Fasudil, an inhibitor of the Rho kinase pathway, was selective in inhibiting nodule formation but not proline incorporation. It was verified that Smad2 phosphorylation, Erk1/2 phosphorylation and p38 MAPK phosphorylation were all induced by TGF-beta1, with Smad 2 phosphorylation peaking at 1-2 h and MAPK phosphorylation at 24-48 h. The effect of TGF-beta1 on phosphorylation of Smad 2 was inhibited by SB431542, on the phosphorylation of p38 MAPK was inhibited by SB203580, and on the phosphorylation of Erk1/2 was inhibited by U0126. ROS generation in response to TGF-beta1, measured as 2,7-dichlorofluorescein-diacetate fluorescence, was inhibited significantly by SB203580 and U0126, implicating both the p38 MAPK and Mekl/2/Erk1/2 signaling pathways. Both pathways also mediated TGF-beta1-induced cellular senescence which was localized to cellular aggregates and mature nodules. CONCLUSION: These data imply that the inhibition of either Smad or MAPK signaling pathways may have a therapeutic benefit in ameliorating the adverse pathological changes associated with aortic valve stenosis.


Assuntos
Estenose da Valva Aórtica/complicações , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Benzamidas/farmacologia , Calcinose/complicações , Senescência Celular , Colágeno/biossíntese , Dioxóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Estenose da Valva Aórtica/etiologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Calcinose/metabolismo , Calcinose/patologia , Células Cultivadas , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Suínos
11.
Circ J ; 75(6): 1506-14, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21532183

RESUMO

BACKGROUND: Statins have been shown to inhibit conduit vessel constrictor responses via the endothelial nitric oxide (NO) pathway. Clinical studies have implicated an effect in microvascular resistance vessels; however, direct effects of therapeutically relevant statin concentrations have not been examined. We examined the effect of acute pravastatin pretreatment on vasoconstrictor responsiveness of isolated rat mesenteric small vessels. METHODS AND RESULTS: Pravastatin (112 nmol/L) pretreatment for 60 min reduced both the potency and maximal constrictor responses to phenylephrine, thromboxane (U46619) and serotonin in small vessels. This effect was abolished by endothelial denudation, NO synthase (NOS) inhibition with N-ω-nitro-L-arginine methyl ester (L-NAME 300 µmol/L) and Akt inhibition (Akt1/2 kinase inhibitor 500 nmol/L), confirming an endothelium-dependent mechanism and implicating a NO-mediated effect via the Akt pathway. Maximal superoxide scavenging with polyethylene glycol-superoxide dismutase (PEG-SOD), 150 U/ml did not influence phenylephrine constrictor responses but potentiated pravastatin's effect, suggesting that the statin did not increase NO bioavailability merely via an antioxidant mechanism. In contrast, pravastatin did not affect endothelin-1 (ET-1) constrictor responses. However, after pre-incubation with a selective endothelin-B (ET(B)) receptor antagonist (BQ788 3 µmol/L) pravastatin inhibited ET-1 constriction, suggesting that its effect is via the same mechanistic pathway as the ET(B) receptor. CONCLUSIONS: In small vessels, pravastatin inhibits constrictor responses by increasing endothelial NO bioavailability via the Akt pathway. Furthermore, ET(B) receptor blockade unmasks this effect in ET-1 constrictor responses.


Assuntos
Células Endoteliais/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Pravastatina/farmacologia , Vasoconstrição/efeitos dos fármacos , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Antagonistas do Receptor de Endotelina B , Endotelina-1/metabolismo , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/metabolismo , Miografia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxidos/metabolismo , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
12.
Br J Pharmacol ; 162(3): 722-32, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20958293

RESUMO

BACKGROUND AND PURPOSE: Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS. EXPERIMENTAL APPROACH: The effects of 8 weeks of treatment with either vitamin D2 at 25,000 IU for 4 days a week alone or in combination with ramipril (0.5 mg·kg⁻¹) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)) and aortic valve:outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function. KEY RESULTS: Treatment with ramipril significantly reduced AV(BS) and improved aortic valve :outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment. CONCLUSIONS AND IMPLICATIONS: Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin-converting enzyme inhibitor.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Estenose da Valva Aórtica/tratamento farmacológico , Estenose da Valva Aórtica/prevenção & controle , Ramipril/farmacologia , Animais , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/fisiologia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/fisiopatologia , Arginina/análogos & derivados , Arginina/sangue , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Ecocardiografia , Inibidores Enzimáticos/sangue , Ergocalciferóis/uso terapêutico , Humanos , Masculino , Coelhos , Vitaminas/uso terapêutico
13.
Curr Opin Cardiol ; 25(4): 329-34, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20535068

RESUMO

PURPOSE OF REVIEW: We focus on the molecular and cellular basis of the improvement in myocardial energetics, which might represent an attractive therapeutic option in some forms of acute and chronic heart disease. RECENT FINDINGS: Myocardial dysfunction, whether related to left ventricular hypertrophy, heart failure or myocardial ischaemia, is frequently associated with impairment of myocardial energy balance. It is now apparent that this energetic impairment plays a pivotal role, not only in the evolution and outcomes of these disorders but also frequently in their pathogenesis. Despite the fact that energetic impairment may arise for many complex reasons, and the difficulty both in assessing the impairment in vivo and in determining its precise mechanism(s), a number of drugs have become available for treatment of ischaemia and heart failure, as well as potentially for limitation of pathological left ventricular hypertrophy, which act primarily by altering myocardial metabolism so as to improve energetic status. Recent studies with perhexiline and trimetazidine, agents which induce a 'metabolic shift' from long-chain fatty acid to glucose utilization, have demonstrated the utility of this therapeutic principle. SUMMARY: There is ongoing need for more complete mechanistic understanding of the 'metabolic agents', as well as for the large-scale clinical trials of their impact on health outcomes.


Assuntos
Reperfusão Miocárdica , Miocárdio/metabolismo , Acetanilidas/uso terapêutico , Amiodarona/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Imagem de Perfusão do Miocárdio , Miocárdio/citologia , Miocárdio/patologia , Perexilina/uso terapêutico , Piperazinas/uso terapêutico , Ranolazina , Trimetazidina/uso terapêutico , Vasodilatadores/uso terapêutico
14.
Eur J Pharmacol ; 602(1): 28-35, 2009 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-19056377

RESUMO

Calcific aortic stenosis displays some similarities to atherosclerosis including evidence of endothelial dysfunction. Whether nitric oxide (NO), which is produced by valvular endothelium, has direct protective effects extending to calcification processes in aortic valve cells has not previously been examined. In vitro calcifying nodules in porcine aortic valve interstitial cell cultures, formed in response to transforming growth factor-beta1 (TGF-beta1) 5 ng/ml, were inhibited by NO donors DETA-NONOate 5-100 microM, and sodium nitroprusside (SNP) 3 microM. Raising intracellular cGMP concentrations, via 8-bromo cGMP 1 mM or via brain natiuretic peptide and C-type natiuretic peptide 0.1 microM, inhibited TGF-beta1-induced nodule formation, potentially implicating the cGMP pathway in the NO effect. Stimulation of interstitial cells with substance P or calcium ionophone (A23187) caused NO release and increased intracellular cGMP respectively. However in the presence of TGF-beta1 basal levels of NO production via nitric oxide synthase (NOS) were insufficient to affect nodule formation. Increased dihydroethidium (DHE) fluorescence in response to TGF-beta1, which was inhibited by DETA-NONOate and TEMPOL, suggested a role for intracellular superoxide in TGF-beta1 signalling. Moreover, nodule formation was suppressed by superoxide scavengers TEMPOL, hydralazine and polyethylene glycol-superoxide dismutase (PEG-SOD), but not SOD. In conclusion, NO donors, or agents raising intracellular cGMP levels, may protect aortic valve interstitial cells from early events leading to calcification.


Assuntos
Valva Aórtica/citologia , Calcinose/metabolismo , Calcinose/patologia , Doadores de Óxido Nítrico/farmacologia , Vasodilatadores/farmacologia , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Células Cultivadas , GMP Cíclico/metabolismo , Sequestradores de Radicais Livres/farmacologia , Ionóforos/farmacologia , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Nitroprussiato/farmacologia , Suínos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/metabolismo
15.
Eur J Pharmacol ; 590(1-3): 290-6, 2008 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-18585377

RESUMO

Understanding of the pathophysiology of aortic valve stenosis (AVS) and finding potentially effective treatments are impeded by the lack of suitable AVS animal models. A previous study demonstrated the development of AVS in rabbits with vitamin D(2) and cholesterol supplementation without any hemodynamic changes in the cholesterol supplemented group alone. The current study aimed to determine whether AVS develops in an animal model with vitamin D(2) supplementation alone, and to explore pathophysiological mechanisms underlying this process. The effects of 8 weeks' treatment with vitamin D(2) alone (n=8) at 25,000 IU/4 days weekly on aortic valve structure and function were examined in male New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)), transvalvular velocity, and transvalvular pressure gradient were utilized to quantitate changes in valve structure and function. Valvular histology/immunochemistry and function were examined after 8 weeks. Changes in valves were compared with those in endothelial function and in valvular measurement of thioredoxin-interacting protein (TXNIP), a marker/mediator of reactive oxygen species-induced oxidative stress. Vitamin D(2) treated rabbits developed AVS with increased AV(BS) (17.6+/-1.4 dB vs 6.7+/-0.8 dB, P<0.0001), increased transvalvular velocity and transvalvular pressure gradient (both P<0.01 via 2-way ANOVA) compared to the control group. There was associated valve calcification, lipid deposition and macrophage infiltration. Endothelial function was markedly impaired, and intravalvular TXNIP concentration increased. In this model, vitamin D(2) induces the development of AVS with histological features similar to those of early AVS in humans and associated endothelial dysfunction/redox stress. AVS development may result from the loss of nitric oxide suppression of TXNIP expression.


Assuntos
Estenose da Valva Aórtica/induzido quimicamente , Proteínas de Transporte/fisiologia , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Ergocalciferóis/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Estenose da Valva Aórtica/fisiopatologia , Proteínas de Transporte/análise , Ecocardiografia , Hipercolesterolemia/complicações , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Estresse Oxidativo , Coelhos
16.
Toxicol Sci ; 99(2): 605-11, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17652335

RESUMO

Anabolic steroid abuse has been associated with thrombosis and arteriosclerosis, both of which predispose to myocardial ischemia and infarction. However, there are reports of sudden cardiac death in the absence of thrombus and atheroma following anabolic steroid use. Although treatment with the commonly abused steroid, nandrolone, has been shown to decrease recovery of systolic function following ischemia in isolated rat hearts, it is unknown whether anabolic steroids can increase the incidence of fatal arrhythmia associated with cardiac ischemia. Anesthetized male Sprague-Dawley rats were administered vehicle or nandrolone (10-160 microg/kg/min iv) 10 min prior to 15-min occlusion of the left anterior descending coronary artery followed by 10-min reperfusion. Nandrolone, in this dose range, did not significantly change heart rate, blood pressure, or cardiac rhythm in the absence of ischemia. However, the fraction of rats surviving ischemia was significantly (p < 0.05) decreased by nandrolone at both 40 and 160 microg/kg/min, while survival time during ischemia was decreased significantly (p < 0.001) by nandrolone 160 microg/kg/min. An increase (p < 0.05) in the duration of ventricular fibrillation was noted at the highest compared to the lowest dose of nandrolone, corresponding to a significant increase in the fraction of rats experiencing ventricular fibrillation (p < 0.01). Nandrolone had no effect on the frequency or duration of ventricular fibrillation or survival time during reperfusion. Although the mechanisms underlying these effects are currently unclear, they indicate that exposure to anabolic steroids in combination with transient reductions in coronary blood flow may explain some reports of sudden cardiac death in anabolic steroid users.


Assuntos
Arritmias Cardíacas/etiologia , Isquemia Miocárdica/complicações , Nandrolona/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Reperfusão Miocárdica , Nandrolona/sangue , Ratos , Ratos Sprague-Dawley
17.
Eur J Pharmacol ; 560(1): 49-55, 2007 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-17292880

RESUMO

Perhexiline, a "metabolic" anti-anginal agent currently under investigation in management of congestive heart failure and acute coronary syndromes improves platelet nitric oxide responsiveness in patients with impaired responsiveness. The current study investigated possible interactions between perhexiline and the nitric oxide donor nitroglycerin on arterial stiffness, neutrophil superoxide release and on platelet nitric oxide responsiveness. Patients (n=39) with stable angina pectoris, awaiting cardiac catheterization were randomized to additional perhexiline or unchanged drug therapy; all patients received nitroglycerin infusion for 2 h. Vasomotor responses to perhexiline and combined perhexiline/nitroglycerin were examined using changes in augmentation index, measured via applanation tonometry. Neutrophil superoxide release was measured ex vivo utilizing lucigenin mediated chemiluminescence and effect of perhexiline on inhibition of platelet aggregation by sodium nitroprusside was also measured. Perhexiline alone did not affect augmentation index, neutrophil superoxide release, or ex vivo platelet sodium nitroprusside response. Nitroglycerin decreased augmentation index (P<0.01) and superoxide release (P<0.05). Magnitude of inhibition of superoxide release was significantly enhanced by perhexiline pre-treatment (P<0.05); however perhexiline had no effect on magnitude of vasomotor response to nitroglycerin. In conclusion, perhexiline exerts no effects on arterial stiffness and does not potentiate nitroglycerin induced dilatation. In patients with normal platelet function perhexiline does not affect platelet nitric oxide responsiveness. In vivo low dose nitroglycerin inhibits neutrophil superoxide release; this effect is potentiated by pre-treatment with perhexiline. These "anti-inflammatory" effects of nitroglycerin may contribute to utility in acute coronary syndromes and congestive heart failure.


Assuntos
Angina Pectoris/tratamento farmacológico , Nitroglicerina/uso terapêutico , Perexilina/farmacologia , Vasodilatadores/farmacologia , Artérias/efeitos dos fármacos , Artérias/fisiologia , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Interações Medicamentosas , Feminino , Humanos , Luminescência , Masculino , Manometria , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Perexilina/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária , Superóxidos/metabolismo , Vasodilatadores/uso terapêutico
19.
Eur J Pharmacol ; 531(1-3): 13-9, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16413015

RESUMO

The prophylactic anti-anginal agent, perhexiline, may also be effective in acute coronary syndromes and advanced aortic valvular stenosis, conditions associated with enhanced inflammation. Its potential effects on superoxide formation via NADPH oxidase were measured by lucigenin-mediated chemiluminescence. Perhexiline inhibited superoxide formation in intact neutrophils stimulated with formyl Met Leu Phe (fMLP) 4 muM or with phorbol myristate acetate (PMA) 162 nM - IC50 2.3 microM (1.5-3.6), n=4. Sub-unit assembly of NADPH oxidase by PMA was unaffected by pretreatment with perhexiline 2 microM, a concentration which reduced superoxide formation by 44+/-5% (n=4) in intact neutrophils. Perhexiline inhibited preassembled neutrophil NADPH oxidase and that in membranes of pig valve interstitial cells, human umbilical vein endothelial cells (HUVECs) and cardiac fibroblasts, but not that in rat aorta (rings or membrane preparations). These data imply that perhexiline inhibits the phagocytic NADPH oxidase directly, and that pig aortic valvular interstitial cells possess a similar enzyme, a conclusion supported by immunohistochemical localisation of the gp91phox subunit in these cells. However further study is required to clarify the effect of perhexiline on different NADPH oxidase isoforms particularly in the vasculature.


Assuntos
Aorta Torácica/efeitos dos fármacos , Valva Aórtica/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Perexilina/farmacologia , Superóxidos/metabolismo , Angina Pectoris/prevenção & controle , Animais , Animais Recém-Nascidos , Aorta Torácica/metabolismo , Valva Aórtica/metabolismo , Fármacos Cardiovasculares/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Sequestradores de Radicais Livres/farmacologia , Humanos , Técnicas In Vitro , Medições Luminescentes , Masculino , N-Formilmetionina Leucil-Fenilalanina/farmacologia , NADP/farmacologia , NADPH Oxidases/metabolismo , Neutrófilos/metabolismo , Ratos , Ratos Wistar , Superóxidos/química , Suínos , Acetato de Tetradecanoilforbol/farmacologia
20.
J Cardiovasc Pharmacol ; 46(6): 849-55, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16306812

RESUMO

The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.


Assuntos
Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Perexilina/farmacologia , Animais , Células Cultivadas , Glucose/metabolismo , Glicina/análogos & derivados , Glicina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Oxirredução , Ácido Palmítico/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
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