O papel da angiogênese e da hemólise na úlcera de perna de pessoas com anemia falciforme
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Data
2016-03-07
Autores
Oliveira, Renan Garcia de [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A anemia falciforme (AF) é uma anemia hemolítica hereditária, autossômica recessiva, causada pela mutação em um único nucleotídeo no gene da beta globina (HBB:c.20A>T). Essa alteração resulta na produção de uma hemoglobina anormal, denominada hemoglobina S (Hb S). Em condições de hipóxia, essas hemoglobinas se polimerizam dentro do eritrócito, ocasionando alteração em sua estrutura e resultando na formação de eritrócitos falciformes, que são menos flexíveis, aderem ao endotélio e são propensos à hemólise, favorencendo os dois principais eventos fisiopatológicos da AF, a hemólise e a vasoclusão, que dirigem os processos envolvidos nos diferentes tipos de manifestações clínicas que esses indivíduos podem apresentar ao longo da vida. A úlcera de perna é uma condição clínica frequente nesses indivíduos e a etiologia dessa complicação pode estar relacionada a eventos hemolíticos e angiogênicos. Dessa forma, o objetivo desse trabalho foi avaliar a presença de marcadores hemolíticos e de angiogenese em pacientes com AF, na presença ou ausência de úlcera de perna, a fim de contribuir com o entendimento a respeito dos mecanismos envolvidos na ocorrência de tal manifestação clínica. Para isso, foram avaliados os polimorfismos que regulam a expressão de proteínas que participam do processo de angiogênese, como TGF-β1, VEGFA1 e HIF-1α; os marcadores de hemólise, como níveis de hemoglobina (Hb), lactato desidrogenase (LDH), bilirrubina indireta (BI), aspartato aminotransferase (AST) e contagem de reticulócitos (RET); além da síntese proteica de VEGFA1, TGFB1 e HIF1A, fatores importantes para a angiogênese e regulação do processo de cura das feridas. Os resultados obtidos evidenciam significativa relação da gravidade da anemia com a ocorrência de úlcera de perna em pessoas com a AF. No entanto, o mesmo não ocorreu com os polimorfismos que regulam a expressão das proteínas que participam da angiogênese, em que não foi observada relação, de risco ou de proteção, desses polimorfismos com a ocorrência de úlcera de perna na AF. Além disso, a avaliação dos níveis plasmáticos das proteínas VEGFA1, TGFB1 e HIF1A, indica que a úlcera de perna em pessoas com AF está associado a um quadro pró-angiogênico, evidenciado pelos altos níveis de VEGFA1 e TGFB1 nesses indivíduos, em comparação as pessoas com AF que não apresentam essa complicação clínica, o que resulta em prejuízo a homeostase do processo de cura da ferida.
The sickle cell anemia (SCA) is an inherited hemolytic anemia, autosomal recessive, caused by mutations in a single nucleotide in the beta globin gene (HBB:c.20A>T). This change results in production of an abnormal hemoglobin called hemoglobin S (Hb S). In hypoxic conditions, these hemoglobins polymerize within the erythrocyte, causing changes in their structure and resulting in the formation of sickle erythrocytes, which are less flexible, adhere to the endothelium and are prone to hemolysis, favoring the two main pathophysiological events of alpha hemolysis and vasoclusão, driving the processes involved in different types of clinical manifestations that these individuals may have lifelong. The leg ulcer is a common clinical condition of these individuals and the etiology of this complication may be related to haemolytic and angiogenic events. Thus, the objective of this study was to evaluate the presence of hemolytic markers and angiogenesis in patients with AF in the presence or absence of leg ulcer in order to contribute to the understanding of the mechanisms involved in the occurrence of such clinical manifestation. For this, we evaluated the polymorphisms that regulate the expression of proteins involved in the angiogenesis process, such as TGF-β1, VEGFA1 and HIF-1α; the markers of hemolysis, such as hemoglobin (Hb), lactate dehydrogenase (LDH), bilirubin indirect (BI), aspartate aminotransferase (AST) and reticulocyte count (RET); addition of protein synthesis of VEGFA1, TGFB1 and HIF1A, important factors for regulating angiogenesis and the healing process of wounds. The results show a significant relationship between severity of anemia with the occurrence of leg ulcers in people with SCA. However, the same did not occur with the polymorphisms that regulate the expression of proteins involved in angiogenesis, in which no relationship was observed, risk or protection of these polymorphisms with the occurrence of leg ulcer in SCA. Moreover, the evaluation of plasma levels of proteins VEGFA1, TGFB1 and HIF1A, indicates that leg ulcers in sickle cell patients is associated with a pro-angiogenic state, as evidenced by the high levels of VEGFA1 and TGFB1 these individuals, compared to individuals with SCA who do not have this clinical complication, which results in injury homeostasis of the wound healing process.
The sickle cell anemia (SCA) is an inherited hemolytic anemia, autosomal recessive, caused by mutations in a single nucleotide in the beta globin gene (HBB:c.20A>T). This change results in production of an abnormal hemoglobin called hemoglobin S (Hb S). In hypoxic conditions, these hemoglobins polymerize within the erythrocyte, causing changes in their structure and resulting in the formation of sickle erythrocytes, which are less flexible, adhere to the endothelium and are prone to hemolysis, favoring the two main pathophysiological events of alpha hemolysis and vasoclusão, driving the processes involved in different types of clinical manifestations that these individuals may have lifelong. The leg ulcer is a common clinical condition of these individuals and the etiology of this complication may be related to haemolytic and angiogenic events. Thus, the objective of this study was to evaluate the presence of hemolytic markers and angiogenesis in patients with AF in the presence or absence of leg ulcer in order to contribute to the understanding of the mechanisms involved in the occurrence of such clinical manifestation. For this, we evaluated the polymorphisms that regulate the expression of proteins involved in the angiogenesis process, such as TGF-β1, VEGFA1 and HIF-1α; the markers of hemolysis, such as hemoglobin (Hb), lactate dehydrogenase (LDH), bilirubin indirect (BI), aspartate aminotransferase (AST) and reticulocyte count (RET); addition of protein synthesis of VEGFA1, TGFB1 and HIF1A, important factors for regulating angiogenesis and the healing process of wounds. The results show a significant relationship between severity of anemia with the occurrence of leg ulcers in people with SCA. However, the same did not occur with the polymorphisms that regulate the expression of proteins involved in angiogenesis, in which no relationship was observed, risk or protection of these polymorphisms with the occurrence of leg ulcer in SCA. Moreover, the evaluation of plasma levels of proteins VEGFA1, TGFB1 and HIF1A, indicates that leg ulcers in sickle cell patients is associated with a pro-angiogenic state, as evidenced by the high levels of VEGFA1 and TGFB1 these individuals, compared to individuals with SCA who do not have this clinical complication, which results in injury homeostasis of the wound healing process.
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Palavras-chave
Doença falciforme, Úlcera de membro inferior, Anemia hemolítica, Isquemia tecidual, Estímulo angiogênico, Sickle cell disease, Sickle cell leg ulcer, Hemolytic anemia, Tissue ischemia, Angiogenic stimulus