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1.
Exp Gerontol ; 43(7): 615-622, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18468826

RESUMO

Numerous murine models are available for the study of the human aging process. Most of these models are based on known mutations that cause progeroid disease in humans or are involved in DNA repair and cell senescence. While these models certainly have contributed to our knowledge of age-related diseases, none adequately represent the range of human ailments involving cardiovascular and neurocognitive deterioration. In the current review, we summarize the available murine models of aging to date. We then discuss the known involvement of apolipoprotein E (ApoE) in various symptoms of the human aging process and describe the corresponding age-related phenotypes presented by the ApoE knockout mouse.


Assuntos
Envelhecimento/fisiologia , Apolipoproteínas E/fisiologia , Longevidade/fisiologia , Idoso , Envelhecimento/genética , Animais , Apolipoproteínas E/genética , Doenças Cardiovasculares/genética , Reparo do DNA , Demência/genética , Modelos Animais de Doenças , Predisposição Genética para Doença , Glucuronidase/genética , Humanos , Proteínas Klotho , Camundongos , Camundongos Knockout , Fenótipo
2.
Circ Res ; 99(8): 801-15, 2006 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-17038650

RESUMO

Over the last 4 decades, heart transplantation (HTx) has evolved as a mainstream therapy for heart failure. Approximately half of patients needing HTx have organ failure consequent to atherosclerosis. Despite advances in immunosuppressive drugs, long-term success of HTx is limited by the development of a particular type of coronary atherosclerosis, referred to as cardiac allograft vasculopathy (CAV). Although the exact pathogenesis of CAV remains to be established, there is strong evidence that CAV involves immunologic mechanisms operating in a milieu of nonimmunologic risk factors. The immunologic events constitute the principal initiating stimuli, resulting in endothelial injury and dysfunction, altered endothelial permeability, with consequent myointimal hyperplasia and extracellular matrix synthesis. Lipid accumulation in allograft arteries is prominent, with lipoprotein entrapment in the subendothelial tissue, through interactions with proteoglycans. The apparent endothelial "intactness" in human coronary arteries of the transplanted heart suggest that permeability and function of the endothelial barrier altered. Various insults to the vascular bed result in vascular smooth muscle cell (SMC) activation. Activated SMCs migrate from the media into the intima, proliferate, and elaborate cytokines and extracellular matrix proteins, resulting in luminal narrowing and impaired vascular function. Arteriosclerosis is a broad term that is used to encompass all diseases that lead to arterial hardening, including native atherosclerosis, postangioplasty restenosis, vein bypass graft occlusion, and CAV. These diseases exhibit many similarities; however, they are distinct from one another in numerous ways as well. The present review summarizes the current understanding of the risk factors and the pathophysiological similarities and differences between CAV and atherosclerosis.


Assuntos
Arteriosclerose/fisiopatologia , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/fisiopatologia , Transplante de Coração/efeitos adversos , Animais , Arteriosclerose/patologia , Doença da Artéria Coronariana/patologia , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Matriz Extracelular/metabolismo , Humanos , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso , Fatores de Risco
3.
Am J Transplant ; 5(3): 494-9, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15707403

RESUMO

Endothelial cell death induced by cytotoxic T cells is a key initiating event in the development of transplant vascular disease (TVD), the leading cause of late solid organ transplant failure. We studied the role of the granzyme B (GrB) pathwaye, which is one of the main mechanisms by which T cells induce apoptosis of allogeneic targets, in the pathogenesis of TVD. Granzyme B, in combination with perforin (pfn), induced apoptosis of cultured endothelial cells. In hearts transplanted into GrB knockout (GrB-KO) mice, there was a similar level of vasculitis as compared to WT mice, indicating that GrB does not affect immune infiltration into allograft arteries. However, there was a significant reduction in luminal narrowing of allograft arteries from GrB-KO mice as compared to WT recipients. These results indicate that GrB plays a role in endothelial cell death in allograft arteries and in the resultant development of TVD.


Assuntos
Apoptose/fisiologia , Células Endoteliais/enzimologia , Sobrevivência de Enxerto/fisiologia , Serina Endopeptidases/metabolismo , Animais , Artérias/enzimologia , Artérias/patologia , Células Endoteliais/metabolismo , Granzimas , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Perforina , Proteínas Citotóxicas Formadoras de Poros , Transplante Homólogo
4.
Chem Biol ; 11(1): 57-67, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15112995

RESUMO

We conducted 16 parallel in vitro selection experiments to isolate catalytic DNAs from a common DNA library for the cleavage of all 16 possible dinucleotide junctions of RNA incorporated into a common DNA/RNA chimeric substrate sequence. We discovered hundreds of sequence variations of the 8-17 deoxyribozyme--an RNA-cleaving catalytic DNA motif previously reported--from nearly all 16 final pools. Sequence analyses identified four absolutely conserved nucleotides in 8-17. Five representative 8-17 variants were tested for substrate cleavage in trans, and together they were able to cleave 14 dinucleotide junctions. New 8-17 variants required Mn2+ to support their broad dinucleotide cleavage capabilities. We hypothesize that 8-17 has a tertiary structure composed of an enzymatic core executing catalysis and a structural facilitator providing structural fine tuning when different dinucleotide junctions are given as cleavage sites.


Assuntos
DNA de Cadeia Simples/metabolismo , Fosfatos de Dinucleosídeos/metabolismo , Catálise , DNA/química , DNA/metabolismo , DNA Catalítico/química , DNA Catalítico/classificação , DNA Catalítico/metabolismo , DNA de Cadeia Simples/química , Fosfatos de Dinucleosídeos/química , Magnésio/metabolismo , Manganês/metabolismo , Modelos Biológicos , Estrutura Molecular , RNA/química , RNA/metabolismo , RNA Catalítico/metabolismo , Análise de Sequência de DNA , Relação Estrutura-Atividade , Especificidade por Substrato
5.
Can J Physiol Pharmacol ; 82(12): 1053-60, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15644946

RESUMO

The cytochrome p450 (CYP) superfamily is responsible for the oxidation, peroxidation, and (or) reduction of vitamins, steroids, xenobiotics, and the majority of cardiovascular drugs in an oxygen- and NADPH-dependent manner. Although hepatic CYP have been studied extensively, the role of CYP in cardiovascular physiology and disease is poorly understood. Increasing evidence suggests that these enzymes play an important role in the pathogenesis of a number of cardiovascular diseases. The current review summarizes the understanding as to the role that dysregulated CYP expression and (or) activity may play in the onset and progression of cardiovascular disease.


Assuntos
Doenças Cardiovasculares/enzimologia , Sistema Enzimático do Citocromo P-450/fisiologia , Animais , Homeostase/fisiologia , Humanos , Neovascularização Patológica/fisiopatologia
6.
Br J Pharmacol ; 137(8): 1163-72, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12466225

RESUMO

1. The recombinant human prostaglandin D(2) (PGD(2)) receptor, hCRTH2, has been expressed in HEK293(EBNA) and characterized with respect to radioligand binding and signal transduction properties. High and low affinity binding sites for PGD(2) were identified in the CRTH2 receptor population by saturation analysis with respective equilibrium dissociation constants (K(D)) of 2.5 and 109 nM. This revealed that the affinity of PGD(2) for CRTH2 is eight times less than its affinity for the DP receptor. 2. Equilibrium competition binding assays revealed that of the compounds tested, only PGD(2) and several related metabolites bound with high affinity to CRTH2 (K(i) values ranging from 2.4 to 34.0 nM) with the following rank order of potency: PGD(2)>13,14-dihydro-15-keto PGD(2)>15-deoxy-Delta(12,14)-PGJ(2)>PGJ(2)>Delta(12)-PGJ(2)>15(S)-15 methyl-PGD(2). This is in sharp contrast with the rank order of potency obtained at DP : PGD(2)>PGJ(2)>Delta(12)-PGJ(2)>15-deoxy-Delta(12,14)-PGJ(2) >>>13,14-dihydro-15-keto-PGD(2). 3. Functional studies demonstrated that PGD(2) activation of recombinant CRTH2 results in decrease of intracellular cAMP in a pertussis toxin-sensitive manner. Therefore, we showed that CRTH2 can functionally couple to the G-protein G(alphai/o). PGD(2) and related metabolites were tested and their rank order of potency followed the results of the membrane binding assay. 4. By Northern blot analysis, we showed that, besides haemopoietic cells, CRTH2 is expressed in many other tissues such as brain, heart, thymus, spleen and various tissues of the digestive system. In addition, in situ hybridization studies revealed that CRTH2 mRNA is expressed in human eosinophils. Finally, radioligand binding studies demonstrated that two eosinophilic cell lines, butyric acid-differentiated HL-60 and AML 14.3D10, also endogenously express CRTH2.


Assuntos
Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Células HL-60 , Humanos , RNA Mensageiro/biossíntese , RNA Mensageiro/metabolismo , Receptores Imunológicos/agonistas , Receptores Imunológicos/biossíntese , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/biossíntese , Receptores de Prostaglandina/fisiologia , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Transfecção
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