RESUMEN
Genetic factors strongly contribute to the pathogenesis of sporadic Alzheimer's disease (AD). Nevertheless, genome-wide association studies only yielded single nucleotide polymorphism loci of moderate importance. In contrast, microsatellite repeats are functionally less characterized structures within our genomes. Previous work has shown that endothelin-converting enzyme-1 (ECE-1) is able to reduce amyloid ß content. Here we demonstrate that a CpG-CA repeat within the human ECE-1c promoter is highly polymorphic, harbors transcriptional start sites, is able to recruit the transcription factors poly(ADP-ribose) polymerase-1 and splicing factor proline and glutamine-rich, and is functional regarding haplotype-specific promoter activity. Furthermore, genotyping of 403 AD patients and 444 controls for CpG-CA repeat length indicated shifted allelic frequency distributions. Sequencing of 245 haplotype clones demonstrated that the overall CpG-CA repeat composition of AD patients and controls is distinct. Finally, we show that human and chimpanzee [CpG](m)-[CA](n) ECE-1c promoter repeats are genetically and functionally distinct. Our data indicate that a short genomic repeat structure constitutes a novel core promoter element, coincides with human evolution, and contributes to the pathogenesis of AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Ácido Aspártico Endopeptidasas/genética , Evolución Biológica , Metaloendopeptidasas/genética , Repeticiones de Microsatélite/genética , Regiones Promotoras Genéticas/genética , Transcripción Genética/genética , Animales , Western Blotting , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/fisiopatología , Cromatografía en Gel , ADN/genética , ADN/aislamiento & purificación , Ensayo de Cambio de Movilidad Electroforética , Enzimas Convertidoras de Endotelina , Genotipo , Humanos , Ensayos de Protección de Nucleasas , Pan troglodytes , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/genética , ARN/genética , ARN/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The present study aimed to explore the anti-inflammatory effects and peroxisome proliferator-activated receptor-γ (PPARγ)-activating properties of the angiotensin type 1 receptor blocker telmisartan by analysis of serum interleukin 6 levels and monocytic PPARγ target gene expression in drug-naïve patients with the metabolic syndrome. This was a 14-week, randomized, double-blind, placebo-controlled 2-center study with telmisartan 80 mg/d and telmisartan 160 mg/d in 54 patients with the metabolic syndrome. In addition to clinical laboratory measurements, peripheral monocytes were extracted by negative isolation using a Dynal Monocyte kit to evaluate ligand-activated PPARγ target gene expression (CD36 and CD163) at baseline and study end using quantitative real-time RT-PCR. In this low-risk patient population, telmisartan (80 and 160 mg) treatment did not significantly affect serum interleukin 6 levels. Expression of the PPARγ target gene CD36 in monocytes was markedly induced by telmisartan from baseline to study end (telmisartan 80 mg: 2.3±1.5-fold change versus placebo [P value not significant]; telmisartan 160 mg: 3.5±0.9-fold change versus placebo [P<0.05]). The recently reported PPARγ target gene CD163 was slightly induced by telmisartan (telmisartan 80 mg: 1.1±0.3-fold change versus placebo [P value not significant]; telmisartan 160 mg: 1.4±0.4-fold change versus placebo [P value not significant]), which did not reach statistical significance. This is the first clinical description of monocytic PPARγ target gene regulation with high-dose telmisartan treatment. These data implicate that the angiotensin type 1 receptor blocker telmisartan activates PPARγ in circulating monocytes of patients with the metabolic syndrome.
Asunto(s)
Bloqueadores del Receptor Tipo 2 de Angiotensina II/farmacología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Bencimidazoles/farmacología , Benzoatos/farmacología , Antígenos CD36/metabolismo , Síndrome Metabólico/metabolismo , Monocitos/metabolismo , PPAR gamma/metabolismo , Receptores de Superficie Celular/metabolismo , Adulto , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Interleucina-6/sangre , Masculino , Síndrome Metabólico/patología , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Monocitos/patología , PPAR gamma/agonistas , Pioglitazona , Telmisartán , Tiazolidinedionas/farmacologíaRESUMEN
AIMS: The present study aimed to explore the impact of the angiotensin type 1 receptor blocker valsartan (VAL) on inflammatory-/lipid-/glucose parameters in hypertensive diabetic patients with and without coronary artery disease (CAD). METHODS: This was a 16-week, randomized, double-blind, placebo-controlled two-center study with VAL 320 mg/d in 109 hypertensive diabetic patients (n=56 non-CAD; n=53 CAD). RESULTS: VAL treatment did not significantly affect serum interleukin-6 (IL-6) or tumor necrosis factor alpha (TNFalpha) levels in the overall study population but significantly reduced serum IL-6 in the subgroup with high inflammatory load at baseline (IL-6>median (2.0 ng/L), n=54: [median, ng/L]): VAL: from 3.5 to 2.4; placebo: from 3.2 to 3.5; p=0.035). VAL significantly lowered total- and LDL-cholesterol in the whole study population: [median, mg/dL]: total cholesterol: VAL: from 178 to 168; placebo: from 174 to 173, p=0.039; LDL-cholesterol: VAL: from 96 to 90, placebo: from 102 to 103, p=0.006, whereas glycemic parameters were not affected. CONCLUSIONS: The present study demonstrates significant anti-inflammatory efficacy of VAL in hypertensive diabetic patients with enhanced inflammatory burden. High-dose VAL therapy significantly lowered total- and LDL-cholesterol levels. The combined actions of cholesterol and blood pressure lowering by VAL may provide additional clinical benefits for these high-risk patients.