Identificação de eventos moleculares associados à reestenose coronariana
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Data
2017-08-28
Autores
Lara, Juliana Rodrigues [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Atualmente, o procedimento mais utilizado para o tratamento das lesões coronarianas é a angioplastia com implante de stent. Embora existam vantagens com esse procedimento, a reestenose continua sendo um dos principais limitadores do sucesso terapêutico. Sabe-se que inflamação, com acúmulo de células mononucleares ativadas, pode contribuir para o desenvolvimento da reestenose. Assim, estratégias para a identificação de biomarcadores de risco e para a redução das taxas de reestenose representam desafios na área da cardiologia intervencionista. Desta forma, o presente estudo teve como objetivos a identificação de possíveis marcadores genéticos de risco (polimorfismo dos genes MMP-2, MMP-3, MMP-9 -1562, MMP-9 Arg 279 Gln, CYP2C19*2, NOS3 e IL-6), bem como a avaliação de eventos moleculares e bioquímicos (lesões oxidativas no DNA, perfil de expressão gênica e de citocinas) que possam estar envolvidos no desenvolvimento da reestenose. Foram avaliados 330 indivíduos, 220 pacientes coronarianos com e sem reestenose após implante de stent e 110 indivíduos controles (sem implante de stent e com obstrução coronariana menor que 20%). Os resultados mostraram aumento significativo de danos no DNA de células do sangue periférico nos pacientes com reestenose intra-stent, mas nenhuma alteração nos níveis plasmáticos de citocinas (IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α). Com relação aos polimorfismos gênicos, os dados mostraram que o alelo G do gene MMP-9 (Arg279Gln) foi mais frequente nos pacientes coronarianos com reestenose intra-stent. A análise de perfil de genes de células mononucleares do sangue periférico revelou alvos potenciais para inibição da reestenose intra-stent. Com relação aos pacientes com obstrução arterial < 20% (grupo controle) foram 493 (400 hiperexpressos e 93 hipoexpressos) e 21 (6 hiperexpressos e 15 hipoexpressos) transcritos diferencialmente expressos respectivamente em pacientes sem e com reestenose intra-stent. Entre os pacientes com e sem reestenose, foram 243 transcritos diferencialmente expressos (91 hiperexpressos e 152 hipoexpressos). A ontologia genética mostrou que nos pacientes com reestenose dentre os processos biológicos com maior número de genes diferencialmente expressos envolvidos estavam os relacionados ao reparo do DNA, diferenciação de células Tα e β, resposta celular à IL-4, produção de citocinas, regulação da transcrição, regulação do metabolismo lipídico, divisão celular, organização da matriz extracelular, migração de leucócitos, cicatrização de feridas, regulação positiva da angiogênese, coagulação sanguínea, regulação da apoptose de células endoteliais e formação de plaquetas. Concluindo, nossos resultados fornecem base para novas hipóteses e testes para o claro entendimento dos mecanismos de reestenose intra-stent e para novas estratégias de tratamento.
Currently, angioplasty is the most commonly procedure used for the treatment of flow limitation in coronary arteries. Nevertheless, in-stent restenosis continues to remain the principal reason for treatment failure after contemporary coronary stenting. It is known that inflammation, with the accumulation of activated mononuclear cells, may contribute to the development of restenosis. Therefore, strategies for the identification of risk biomarkers and for the reduction of restenosis rates are challenges in the field of interventional cardiology. The present study aimed to identify genetic markers associated to restenosis. DNA damage, gene expression profile and gene polymorphisms (MMP-2, MMP-3, MMP-9 -1562, MMP-9 Arg 279 Gln, CYP2C19 * 2, NOS3 and IL- 6) were evaluated. A total of 330 subjects, 220 coronary patients with or without restenosis after stent implantation, and 110 control subjects (without stent implantation and coronary obstruction of less than 20%) were invited to participate in this study. Results showed significant increase of DNA damage in peripheral blood cells of patients with intra-stent restenosis, and no alteration in the plasma cytokines concentration (IL-1β, IL-6, IL- 8, IL-10, IL-12, TNF- α). Regarding the gene polymorphisms, data showed that G allele of MMP-9 (Arg279Gln) was more frequent in coronary patients with intrastent restenosis. In the gene profiling analysis of mononuclear cells from peripheral blood 243 probesets with differential expression were identified between patients with and without restenosis, and 21 and 493 between patients without stenting coronary and those with and without in stent restenosis, respectively. The genes identified have varied functions, including some related to cellular growth and metabolism, DNA repair, cytokine production, regulation of transcription, cell division, extracellular matrix organization, leukocyte migration, regulation of endothelial cell apoptosis, and platelet formation, such as the MMP-9, NFAT5, REL, ATM, FOXO3 and UTS2R genes. Taken together, our results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of in stent restenosis.
Currently, angioplasty is the most commonly procedure used for the treatment of flow limitation in coronary arteries. Nevertheless, in-stent restenosis continues to remain the principal reason for treatment failure after contemporary coronary stenting. It is known that inflammation, with the accumulation of activated mononuclear cells, may contribute to the development of restenosis. Therefore, strategies for the identification of risk biomarkers and for the reduction of restenosis rates are challenges in the field of interventional cardiology. The present study aimed to identify genetic markers associated to restenosis. DNA damage, gene expression profile and gene polymorphisms (MMP-2, MMP-3, MMP-9 -1562, MMP-9 Arg 279 Gln, CYP2C19 * 2, NOS3 and IL- 6) were evaluated. A total of 330 subjects, 220 coronary patients with or without restenosis after stent implantation, and 110 control subjects (without stent implantation and coronary obstruction of less than 20%) were invited to participate in this study. Results showed significant increase of DNA damage in peripheral blood cells of patients with intra-stent restenosis, and no alteration in the plasma cytokines concentration (IL-1β, IL-6, IL- 8, IL-10, IL-12, TNF- α). Regarding the gene polymorphisms, data showed that G allele of MMP-9 (Arg279Gln) was more frequent in coronary patients with intrastent restenosis. In the gene profiling analysis of mononuclear cells from peripheral blood 243 probesets with differential expression were identified between patients with and without restenosis, and 21 and 493 between patients without stenting coronary and those with and without in stent restenosis, respectively. The genes identified have varied functions, including some related to cellular growth and metabolism, DNA repair, cytokine production, regulation of transcription, cell division, extracellular matrix organization, leukocyte migration, regulation of endothelial cell apoptosis, and platelet formation, such as the MMP-9, NFAT5, REL, ATM, FOXO3 and UTS2R genes. Taken together, our results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of in stent restenosis.
Descrição
Palavras-chave
Artérias coronárias, Stents, Dano no DNA, Expressão gênica, Metaloproteases, Polimorfismo