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G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling.

ABSTRACT: Oestrogens are important sex hormones central to health and disease in both genders that have protective effects on the cardiovascular and metabolic systems. These hormones act in complex ways via both genomic and non-genomic mechanisms. The genomic mechanisms are relatively well characterized, whereas the non-genomic ones are only beginning to be explored. Two oestrogen receptors (ER), ER? and ER?, have been described that act as nuclear transcription factors but can also associate with the plasma membrane and influence cytosolic signalling. ER? has been shown to mediate both anti-atherogenic effects and pro-survival effects in pancreatic ?-cells. In recent years, a third membrane-bound ER has emerged, G protein-coupled receptor 30 or G protein-coupled oestrogen receptor 1 (GPER1), which mediates oestrogenic responses in cardiovascular and metabolic regulation. Both GPER1 knock-out models and pharmacological agents are now available to study GPER1 function. These tools have revealed that GPER1 activation may have several beneficial effects in the cardiovascular system including vasorelaxation, inhibition of smooth muscle cell proliferation, and protection of the myocardium against ischaemia/reperfusion injury, and in the metabolic system including stimulation of insulin release and protection against pancreatic ?-cell apoptosis. Thus, GPER1 is emerging as a candidate therapeutic target in both cardiovascular and metabolic disease.

SUBMITTER: Nilsson BO

PROVIDER: S-EPMC3144530 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling.

Nilsson Bengt-Olof BO Olde Björn B Leeb-Lundberg L M Fredrik LM

British journal of pharmacology 20110701 6

Oestrogens are important sex hormones central to health and disease in both genders that have protective effects on the cardiovascular and metabolic systems. These hormones act in complex ways via both genomic and non-genomic mechanisms. The genomic mechanisms are relatively well characterized, whereas the non-genomic ones are only beginning to be explored. Two oestrogen receptors (ER), ERα and ERβ, have been described that act as nuclear transcription factors but can also associate with the pla ...[more]

PMID: 21250980

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Project description:PURPOSE:Oestrogen receptor ? 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 ? 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 ? 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 ? activation effectively protected cardiomyocytes from MI-induced oxidative damage and apoptosis. Furthermore, oestrogen receptor ? 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 ? activation. Nevertheless, all of these cardioprotective effects of oestrogen receptor ? 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 ? activation is effective in ameliorating MI-induced cardiac dysfunction by enhancing Notch1 signalling and that PI3K/Akt signalling is the downstream mediator.

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G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling.

Publications

G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling.

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