RESUMO
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.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Ácido Aspártico Endopeptidases/genética , Evolução Biológica , Metaloendopeptidases/genética , Repetições de Microssatélites/genética , Regiões Promotoras Genéticas/genética , Transcrição Gênica/genética , Animais , Western Blotting , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Cromatografia em Gel , DNA/genética , DNA/isolamento & purificação , Ensaio de Desvio de Mobilidade Eletroforética , Enzimas Conversoras de Endotelina , Genótipo , Humanos , Ensaios de Proteção de Nucleases , Pan troglodytes , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética , RNA/genética , RNA/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo RealRESUMO
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.
Assuntos
Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Antígenos CD36/metabolismo , Síndrome Metabólica/metabolismo , Monócitos/metabolismo , PPAR gama/metabolismo , Receptores de Superfície Celular/metabolismo , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Interleucina-6/sangue , Masculino , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , PPAR gama/agonistas , Pioglitazona , Telmisartan , Tiazolidinedionas/farmacologiaRESUMO
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.