RESUMO
RATIONALE: The heterodimer IL-12 is an inducer of Th1 responses and stimulates INFÆ´ production. Micro-RNA-21 (miR-21) is described as a key regulator of the pro-inflammatory response and has IL-12p35 mRNA as one of its main targets. The IL-12p40 1188A/C genetic variant located in 3'untranslated region (UTR), thus environmentally exposed, has further been reported to modify IL-12 levels. We have previously reported on the lowering effect of cigarette smoke on circulating IL-12 in patients with coronary artery disease (CAD). OBJECTIVES: To explore if cigarette smoking affects IL-12p35, IL-12p40, INFÆ´ and miR-21 gene-expression and further modulates any effect of the IL-12p40 polymorphism on circulating IL-12 levels. METHODS AND RESULTS: The IL-12p40 1188A/C polymorphism was analyzed in 1001 stable CAD patients, of which 330 subjects were included for IL-12p35, IL-12p40 and INFÆ´ gene-expression analyses in circulating leukocytes and 200 were further selected for plasma miR-21 analysis. Smoking associated with lower expression of miR-21 and its target IL-12p35 mRNA (adjusted p<0.05, both) whereas the influence on INFÆ´ expression tended to be high-dose reliant (p = 0.057). The IL-12p40 CC genotype associated with elevated circulating IL-12 levels, however, when stratified according to smoking, only in the non-smoking group (adjusted p < 0.05). Although the markers were mainly downregulated in current smokers, their inter-correlations were potentiated. CONCLUSION: Smoking associated with reduced miR-21 gene-repression and the results can therefore not explain the previously observed reduction in circulating IL-12. Smoking attenuated the IL-12 pro-inflammatory axis in which the investigated IL-12p40 genetic variant may have different clinical impact in smokers vs non-smokers.
Assuntos
Fumar Cigarros , Doença da Artéria Coronariana/etiologia , Regulação da Expressão Gênica , Interleucina-12/genética , MicroRNAs/genética , Adulto , Idoso , Biomarcadores , Fumar Cigarros/efeitos adversos , Doença da Artéria Coronariana/metabolismo , Citocinas/genética , Citocinas/metabolismo , Feminino , Genótipo , Humanos , Interleucina-12/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Polimorfismo GenéticoRESUMO
Although aspirin is effective in secondary prevention in coronary heart disease, new thromboembolic events in patients on aspirin are frequently seen. In trials on aspirin-treated patients, platelet function tests have revealed large variability in platelet aggregation. This phenomenon has been named aspirin resistance, aspirin non-responsiveness or high-on-aspirin residual platelet reactivity. The mechanism of aspirin antiplatelet effect is due to the inhibition of cyclooxygenase-1 enzyme in platelets. In some trials, almost all patients on aspirin have a very low level of serum thromboxane B2, indicating that the measured platelet reactivity in aspirin-treated patients might be due to platelet activation via other pathways, such as ADP or thrombin. The prevalence of real aspirin resistance seems to be very low, and probably the term "high-on-aspirin residual platelet reactivity" should be preferred to describe this phenomenon.