Avaliação da ação da pravastatina sobre o acoplamento da eNOS e produção de óxido nítrico em modelo in vitro de pré-eclâmpsia
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Data
2022-02-24
Autores
Pinheiro, Luísa Machado
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Universidade Estadual Paulista (Unesp)
Resumo
A pré-eclâmpsia (PE) é uma síndrome complexa responsável por alta morbidade e mortalidade materna e perinatal no Brasil e no mundo. As causas e mecanismos pelos quais essa doença se instala ainda não foram totalmente elucidados, no entanto, acredita-se que uma implantação e placentação anormais sejam responsáveis por gerar uma isquemia placentária levando à uma disfunção endotelial generalizada e liberação de fatores placentários na circulação materna. O desequilíbrio entre forças oxidantes e antioxidantes é um dos fatores que contribui para o desenvolvimento dessa disfunção endotelial, como consequência do estresse oxidativo, diminuição da disponibilidade de óxido nítrico e aumento da produção de O2- pela NADPH Oxidase. A enzima Óxido Nítrico Sintase Endotelial (eNOS) por sua vez é responsável pela produção de NO, importante vasodilatador. No entanto, é importante ressaltar que quando desacoplada essa enzima desvia sua produção para O2-, capaz de sequestrar o NO restante, diminuindo ainda mais a sua disponibilidade. Nessa circunstância muitos estudos tem mostrado a pravastatina como potencial fármaco para o tratamento da pré-eclâmpsia, visto que através de seus efeitos pleiotrópicos esse fármaco apresenta provável capacidade em aumentar o acoplamento da eNOS e produção de NO, além de diminuir a atividade da NADPH oxidase, sendo assim eficaz na melhora da disfunção endotelial com promoção de efeitos vasodilatadores. Além disso, o uso da pravastatina como estatina de escolha se justifica por sua baixa lipofilidade e transferência limitada entre mãe e feto, apresentando, portanto, perfil de segurança favorável. Visando observar os efeitos da pravastatina sobre a pré-eclâmpsia, células endoteliais da veia do cordão umbilical humano (HUVECs) serão, então, incubadas com plasma de gestantes pré-eclâmpticas, hipertensas e saudáveis, na presença ou ausência da pravastatina.
Preeclampsia (PE) is a complex syndrome responsible for high maternal and perinatal morbidity and mortality in Brazil and worldwide. The causes and mechanisms by which this disease sets in have not been fully elucidated, however, it is believed that an abnormal implantation and placentation are responsible for generating a placental ischemia leading to a generalized endothelial dysfunction and release of placental factors in the maternal circulation. The imbalance between oxidative and antioxidant forces is one of the factors that contributes to the development of this endothelial dysfunction, as a consequence of oxidative stress, decreased availability of nitric oxide and increased production of O2- by NADPH Oxidase. The enzyme Nitric Oxide Endothelial Synthase (eNOS) on the other hand is responsible for the production of NO, an important vasodilator. However, it is important to notice that when uncoupled, this enzyme changes its production to O2-, capable of sequestering the remaining NO, further reducing its availability. In this circumstance, many studies have shown pravastatin as a potential drug for the treatment of pre-eclampsia, since through its pleiotropic effects this drug is likely to increase eNOS coupling and NO production, in addition to decreasing NADPH oxidase activity, being effective in improving endothelial dysfunction with the promotion of vasodilatory effects. In addition, the use of pravastatin as the statin of choice is justified by its low lipophilicity and limited transfer between mother and fetus, thus presenting a favorable safety profile. In order to observe the effects of pravastatin on pre-eclampsia, human umbilical cord vein endothelial cells (HUVECs) will be incubated with plasma from pre-eclamptic, hypertensive and healthy pregnant women, in the presence or absence of pravastatin.
Preeclampsia (PE) is a complex syndrome responsible for high maternal and perinatal morbidity and mortality in Brazil and worldwide. The causes and mechanisms by which this disease sets in have not been fully elucidated, however, it is believed that an abnormal implantation and placentation are responsible for generating a placental ischemia leading to a generalized endothelial dysfunction and release of placental factors in the maternal circulation. The imbalance between oxidative and antioxidant forces is one of the factors that contributes to the development of this endothelial dysfunction, as a consequence of oxidative stress, decreased availability of nitric oxide and increased production of O2- by NADPH Oxidase. The enzyme Nitric Oxide Endothelial Synthase (eNOS) on the other hand is responsible for the production of NO, an important vasodilator. However, it is important to notice that when uncoupled, this enzyme changes its production to O2-, capable of sequestering the remaining NO, further reducing its availability. In this circumstance, many studies have shown pravastatin as a potential drug for the treatment of pre-eclampsia, since through its pleiotropic effects this drug is likely to increase eNOS coupling and NO production, in addition to decreasing NADPH oxidase activity, being effective in improving endothelial dysfunction with the promotion of vasodilatory effects. In addition, the use of pravastatin as the statin of choice is justified by its low lipophilicity and limited transfer between mother and fetus, thus presenting a favorable safety profile. In order to observe the effects of pravastatin on pre-eclampsia, human umbilical cord vein endothelial cells (HUVECs) will be incubated with plasma from pre-eclamptic, hypertensive and healthy pregnant women, in the presence or absence of pravastatin.
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Palavras-chave
Pré-eclâmpsia, Pravastatina, Acoplamento eNOS