Interactions between NOS3 and HMOX1 on methyldopa responsiveness in preeclampsia.
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Data
2019-03-13
Autores
Pilan, Eliane Graciela
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Universidade Estadual Paulista (Unesp)
Resumo
A pré-eclâmpsia (PE) é a principal causa de mortalidade e morbidade entre as gestantes no Brasil e em vários países. A fisiopatologia desta doença é complexa e envolve vários processos. Um destes, amplamente validado na literatura, relaciona-se a um status oxidativo, onde há prevalência de produção de radicais livres e/ou redução da atividade antioxidante. Apesar destas evidências, a suplementação clínica com antioxidantes (vitamina C e E) não se demonstrou promissora em PE. Recentemente, vem sendo explorado como terapia em várias doenças, a ativação de um fator de transcrição, o NRF2 (do inglês - nuclear factor, erythroid 2-like 2), que atua induzindo a transcrição de diversos genes que promovem a proteção celular através da codificação de proteínas com atividade desintoxicante e antioxidante. Entre elas a heme oxigenase (HO-1) é a mais estudada, pois apresenta efeitos antiapoptóticos, antioxidantes e citoprotetor. Além disso, o aumento do estresse oxidativo na PE pode potencialmente reduzir a biodisponibilidade de óxido nítrico (NO) que pode ser modulado por alguns polimorfismos localizados no gene da óxido nítrico sintase (NOS3). Notavelmente, os haplótipos formados pela combinação de polimorfismos foram associados a diferentes subgrupos de resposta à terapia anti-hipertensiva em PE. No presente estudo, comparamos as distribuições dos polimorfismos localizados nos genes NFE2L2 rs35652124 (C/T) e no gene HMOX1 rs2071746 (A/T) em gestantes com PE que respondem à metildopa ou à terapia anti-hipertensiva total com aqueles encontrados em gestantes com PE que não respondem à metildopa ou a terapia anti-hipertensiva total. Examinamos se estes polimorfismos afetam os níveis plasmáticos de HO-1 nestes grupos. Além disso, analisamos se as interações entre os polimorfismos dos genes NFE2L2, HMOX1 e NOS3 (rs179998 e rs2070744) estão associadas à PE, e com a capacidade de resposta à metildopa e à terapia anti-hipertensiva total. Nossos principais resultados neste estudo são: (1) o genótipo TT de rs2071746 está associado a não responsividade à metildopa em gestantes com PE; (2); O polimorfismo rs2071746 afeta os níveis plasmáticos de HO-1 em pacientes com PE responsivas à metildopa e à terapia anti-hipertensiva total; (3) interações significativas entre os genótipos dos SNPs HMOX1 rs2071746 e NOS3 rs1799983 foram associados à responsividade à metildopa na PE.
Preeclampsia (PE) is the leading cause of mortality and morbidity among pregnant women in Brazil and several countries. Its pathophysiology is complex and involves several processes, including the oxidative stress (increase of free radicals and/or decrease of antioxidant defense). Although evidences, clinical supplementation with vitamins (C and E) was not promising in preeclampsia. Currently, therapeutically the activation of transcription factor, NRF2 (nuclear factor, erythroid 2-like 2), has been explored in several diseases. This factor promote cytoprotection by activates the transcription of several antioxidant and detoxification proteins. Hemeoxigenase-1 (HO-1) is the most studied, because has antiapoptotic, anti-inflammatory and cytoprotection activities. In addition, the increased oxidative stress in PE can potentially reduce the bioavailability of nitric oxide (NO) which may impaired by some SNPs on endothelial nitric oxide synthase (NOS3) gene. Notably, haplotypes formed by the combination of polymorphisms of were associated with different subgroups of response to antihypertensive therapy in PE. Therefore, in the present study we compared the distributions of rs35652124 (C/T) NFE2L2 and rs2071746 (A/T) HMOX1 polymorphisms in PE patients who respond to methyldopa or antihypertensive therapy with those found in PE patients who do not respond to methyldopa or total antihypertensive therapy. We also examined whether NFE2L2 and HMOX1 polymorphisms affect plasma HO-1 levels in these subgroups of PE patients. In addition, we examined whether interactions among NFE2L2, HMOX1 and NOS3 polymorphisms were associated with PE, and with the responsiveness to methyldopa and total antihypertensive therapy in PE pregnant women. Our main novel findings are (1) the TT genotype of rs2071746 are associated of nonresponse to methyldopa in PE; (2); rs2071746 affect the plasma HO-1 levels in the methyldopa and total antihypertensive responsive group of PE patients and (3) significant interactions between genotypes of the HMOX1 rs2071746 and NOS3 rs1799983 SNPs were found to be associated with responsiveness to methyldopa in PE.
Preeclampsia (PE) is the leading cause of mortality and morbidity among pregnant women in Brazil and several countries. Its pathophysiology is complex and involves several processes, including the oxidative stress (increase of free radicals and/or decrease of antioxidant defense). Although evidences, clinical supplementation with vitamins (C and E) was not promising in preeclampsia. Currently, therapeutically the activation of transcription factor, NRF2 (nuclear factor, erythroid 2-like 2), has been explored in several diseases. This factor promote cytoprotection by activates the transcription of several antioxidant and detoxification proteins. Hemeoxigenase-1 (HO-1) is the most studied, because has antiapoptotic, anti-inflammatory and cytoprotection activities. In addition, the increased oxidative stress in PE can potentially reduce the bioavailability of nitric oxide (NO) which may impaired by some SNPs on endothelial nitric oxide synthase (NOS3) gene. Notably, haplotypes formed by the combination of polymorphisms of were associated with different subgroups of response to antihypertensive therapy in PE. Therefore, in the present study we compared the distributions of rs35652124 (C/T) NFE2L2 and rs2071746 (A/T) HMOX1 polymorphisms in PE patients who respond to methyldopa or antihypertensive therapy with those found in PE patients who do not respond to methyldopa or total antihypertensive therapy. We also examined whether NFE2L2 and HMOX1 polymorphisms affect plasma HO-1 levels in these subgroups of PE patients. In addition, we examined whether interactions among NFE2L2, HMOX1 and NOS3 polymorphisms were associated with PE, and with the responsiveness to methyldopa and total antihypertensive therapy in PE pregnant women. Our main novel findings are (1) the TT genotype of rs2071746 are associated of nonresponse to methyldopa in PE; (2); rs2071746 affect the plasma HO-1 levels in the methyldopa and total antihypertensive responsive group of PE patients and (3) significant interactions between genotypes of the HMOX1 rs2071746 and NOS3 rs1799983 SNPs were found to be associated with responsiveness to methyldopa in PE.
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Palavras-chave
preeclampsia, polymorphisms, Heme oxygenase-1, NOS3, NRF2, therapy antihypertensive