Oestrogen Receptor ß Activation Protects Against Myocardial Infarction via Notch1 Signalling.
Cardiovasc Drugs Ther
; 34(2): 165-178, 2020 04.
Article
em En
| MEDLINE
| ID: mdl-32157565
ABSTRACT
PURPOSE:
Oestrogen receptor ß is believed to exert a cardioprotective effect against ischaemic injury. Nonetheless, the mechanism underlying its protective action remains to be fully elucidated. Recently, increased attention has been focused on Notch1 signalling for ameliorating cardiac ischaemic injury. Here, we hypothesised that oestrogen receptor ß activation attenuates myocardial infarction (MI)-induced cardiac damage by modulating the Notch1 signalling pathway.METHODS:
Male C57BL/6 mice were used to establish an MI model through the ligation of the anterior descending branch of the left coronary artery. Two chemical drugs, 2,3-Bis(4-hydroxyphenyl)-propionitrile (DPN) and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester (DAPT), a specific inhibitor of Notch1 signalling) were administered via intraperitoneal injection to change oestrogen receptor ß and Notch1 activities. Immunohistochemistry, western blot analysis, enzyme-linked immunosorbent assay (Elisa) assessment and echocardiography were used in this study to analyse cardiac oxidative stress, apoptosis, infraction volume, fibrosis and cardiac function.RESULTS:
DPN-mediated oestrogen receptor ß activation effectively protected cardiomyocytes from MI-induced oxidative damage and apoptosis. Furthermore, oestrogen receptor ß activation reduced the infarct size and lowered the levels of myocardial enzymes in the serum, thereby leading to greater overall cardiac function improvement. Ischaemic injury-induced myocardial fibrosis was attenuated by oestrogen receptor ß activation. Nevertheless, all of these cardioprotective effects of oestrogen receptor ß activation were almost abrogated by DAPT administration, i.e. DAPT attenuated the anti-oxidative and anti-apoptotic effects and the decrease in infarct and fibrotic areas and reversed cardiac functional recovery. The levels of phospho-phosphatidylinositol-3-kinase (PI3K) and phospho-protein kinase B (Akt) were increased after DPN administration, and this change was reversed after DAPT was administered.CONCLUSIONS:
All of these new findings indicate that oestrogen receptor ß activation is effective in ameliorating MI-induced cardiac dysfunction by enhancing Notch1 signalling and that PI3K/Akt signalling is the downstream mediator.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Miócitos Cardíacos
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Receptor beta de Estrogênio
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Estrogênios
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Receptor Notch1
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Infarto do Miocárdio
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Nitrilas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cardiovasc Drugs Ther
Assunto da revista:
ANGIOLOGIA
/
CARDIOLOGIA
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TERAPIA POR MEDICAMENTOS
Ano de publicação:
2020
Tipo de documento:
Article