RESUMEN
BACKGROUND: Platelets are believed to play an important role in atherogenesis and the vessel response to vascular injury. The P2Y(12) receptor (P2Y(12)) plays a central role in amplifying platelet aggregation, dense granule and alpha-granule secretion, P-selectin expression, microparticle formation, and procoagulant membrane changes, regardless of the activating stimulus. We hypothesized that P2Y(12) deficiency might reduce the vessel wall response to vascular injury as well as thrombosis in murine vascular injury models. METHODS AND RESULTS: P2Y(12)-deficient (-/-) mice and littermate controls (+/+) were bred on a C57 BL/6 background. In vivo murine models of arterial injury were employed alone and in combination with bone marrow transplantation to investigate the role of P2Y(12) in the vessel wall response to arterial injury and thrombosis. At 21 days after ferric chloride injury, neointima formation in P2Y(12)(-/-) arteries was significantly less than that observed in control strain arteries (P<0.025). In agreement with this, the intima-media ratio was significantly greater in femoral wire-injured arteries from P2Y(12)(+/+) compared with P2Y(12)(-/-) animals (P<0.05). Bone marrow transplantation was used to examine the importance of vessel wall P2Y(12) versus platelet P2Y(12). Analysis of arterial sections from chimeric animals at 21 days after injury revealed a smaller intima-media ratio in -/- to +/+ animals than in the positive (+/+ to +/+) control group (P<0.01). CONCLUSIONS: These data demonstrate a role for platelet P2Y(12) in the vessel wall response to arterial injury and thrombosis. This illustrates the manner in which platelets may contribute to atherogenesis and restenosis.
Asunto(s)
Plaquetas/fisiología , Arteria Femoral/lesiones , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2/metabolismo , Trombosis/fisiopatología , Animales , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Plaquetas/patología , Trasplante de Médula Ósea , Cloruros , Modelos Animales de Enfermedad , Femenino , Arteria Femoral/patología , Arteria Femoral/fisiopatología , Compuestos Férricos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Noxas/toxicidad , Selectina-P/metabolismo , Agregación Plaquetaria/fisiología , Receptores Purinérgicos P2Y12 , Trombosis/patología , Túnica Íntima/lesiones , Túnica Íntima/patología , Túnica Íntima/fisiopatologíaRESUMEN
OBJECTIVE: Mannose binding lectin (MBL) and FcgammaRII (CD32) polymorphisms have both been implicated as candidate susceptibility genes in systemic lupus erythematosus (SLE). The aim of this study was to evaluate the relationship of these polymorphisms with SLE. METHODS: We studied a cohort of 125 SLE patients from Barcelona, Spain and 138 geographically matched controls. Sequence-specific primer-polymerase chain reaction (SSP-PCR) amplification was used to determine CD32 and MBL structural polymorphisms. MBL haplotypes were established using sequence-specific oligonucleotide probing techniques. RESULTS: Patients carried the MBL codon 54 mutant allele more frequently than controls [odds ratio (OR) 2.2; 95% confidence interval (CI) 1.2-4.0; P=0.007] and the haplotype HY W52 W54 W57 was found to be significantly lower in cases compared with controls (OR 0.6; 95% CI 0.4-0.9; P=0.016). CONCLUSION: The MBL gene codon 54 mutant allele appears to be a risk factor for SLE, whilst haplotypes encoding for high levels of MBL are protective against the disease. Differences between controls and patients were not significant when considering the FcgammaRIIa polymorphisms; similar results were observed for renal affectation.
Asunto(s)
Proteínas de Fase Aguda/genética , Proteínas Portadoras/genética , Lupus Eritematoso Sistémico/genética , Receptores de IgG/genética , Proteínas de Fase Aguda/metabolismo , Proteínas Portadoras/metabolismo , ADN/análisis , Frecuencia de los Genes , Haplotipos , Humanos , Lectinas/genética , Lectinas/metabolismo , Lupus Eritematoso Cutáneo/genética , Lupus Eritematoso Cutáneo/metabolismo , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/metabolismo , Nefritis Lúpica/genética , Nefritis Lúpica/metabolismo , Vasculitis por Lupus del Sistema Nervioso Central/genética , Vasculitis por Lupus del Sistema Nervioso Central/metabolismo , Lectinas de Unión a Manosa , Mutación , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Receptores de IgG/metabolismo , EspañaRESUMEN
It was investigated whether a deficiency of mannose-binding lectin (MBL), which binds Aspergillus species avidly in vitro, could account for chronic necrotizing pulmonary aspergillosis (CNPA), which is seen most commonly in nonimmunocompromised patients. Blood samples were obtained from 11 patients (10 white) with CNPA and were compared with blood samples from 82 white control subjects. MBL haplotype profiles were determined by polymerase chain reaction, using sequence-specific primers and sequence-specific oligonucleotide probing techniques. Seven of the 10 white patients with CNPA had MBL haplotypes that encode for low levels of the protein, compared with 25.6% of the white control subjects (P=.004). Presence of the codon 52 mutation was particularly common in patients with CNPA (P=.015), which suggests a greater involvement of this mutation.
Asunto(s)
Aspergilosis/genética , Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad , Enfermedades Pulmonares Fúngicas/genética , Polimorfismo Genético/genética , Alelos , Colectinas , Genotipo , Haplotipos , Humanos , Mutación , NecrosisRESUMEN
Mannose binding lectin (MBL) gene and promoter-region polymorphisms contribute to a reduction in the levels of circulating MBL in a number of ways. Promoter polymorphisms affect the levels of MBL produced, whilst structurally encoding mutations cause non-functional protein to be assembled and subsequently degraded. MBL is important as a protein of the innate immune system in both the clearance of potential pathogens and the activation of the complement cascade. Using variations of SSP-PCR amplifications and SSO probing techniques, we have produced MBL-polymorphism haplotype and genotype profiles of a series of high-level MBL-producing, low-level MBL-producing and random individuals taken from a population of 800 UK Caucasoid controls. Structurally encoding mutant alleles were more frequent within the low-level producing cohort when compared to both high-level producers and the randomly selected sample. However, not all low-level producers could be accounted for by the possession of low-level encoding haplotypes. This may be due to the presence of additional, undetected polymorphisms governing MBL production, or another external factor that may influence the transcriptional regulation of the gene.