G-protein coupled estrogen receptor 1 expression in rat and human heart: Protective role during ischaemic stress

Abstract

Abstract. G-protein coupled estrogen receptor 1, GPER, formerly known as GPR30, is a seven transmembrane domain receptor that mediates rapid estrogen responses in a wide variety of cell types. To date, little is known about the role of GPER during ischaemia/reperfusion injury. In this study, we report both mRNA and protein expression of GPER in the rat and human heart. The role of GPER in estrogen protection against ischaemic stress in the rat heart was also assessed using the isolated Langendorff system. Pre-treatment with 17ß-estradiol (E2) significantly decreased infarct size, (61.48±2.2% to 27.92±2.9% (P<0.001). Similarly, treatment with the GPER agonist G1 prior to 30-min global ischaemia followed by 120-min reperfusion significantly reduced infarct size from 61.48±2.2% to 23.85±3.2% (P<0.001), whilst addition of GPR30 antibody, abolished the protective effect of G1 (infarct size: 55.42±1.3%). The results suggest that GPER under cardiac stress exerts direct protection in the heart and may serve as a potential therapeutic target for cardiac drug therapy. IntroductionEstrogens play critical regulatory roles in the physiology and development of numerous organs through binding to specific receptors (1). The female reproductive system, including the uterus and the breast, are major targets of estrogen actions. In addition, estrogens act on non-reproductive organs such as the brain, liver, and heart. Epidemiological studies have documented a lower incidence of coronary heart disease in premenopausal women compared with age-matched postmenopausal women and compared with men, suggesting a protective role of estrogens at the cardiac level (2,3). This cardioprotective effect has been further corroborated in rodent models (4-8). Two isoforms of nuclear estrogen receptors termed ER· and ERß mediate genomic responses to estrogens, and have distinct, non-overlapping physiological functions. Upon activation, the ligand-activated nuclear estrogen receptor dimerises and can directly interact with estrogen response elements in the promoter region of target genes, leading to activation/repression of gene transcription (9-12).Over the past 20 years many research groups have shown that steroids also act at the cell surface of many target tissues and cell types to initiate rapid responses, via binding to membrane receptors, that frequently do not involve changes in gene transcription (13). GPER represents a third ER in addition to the classical nuclear ER isoforms ER· and ERß. GPER, previously known as GPR30, has been cloned by several research groups initially as an orphan G-protein coupled receptor (GPCR) with a wide distribution in both reproductive and nonreproductive tissues (14-17). Filardo and co-workers suggested that GPER may be associated with estrogen signalling based on their finding that estrogens caused rapid activation of signalling pathways in a breast cancer cell line (SKBR3 cells) that do not express ERs but express GPER (18). Subsequently it was demonstrated independently by two research groups that recombinan...

Non-genomic Effects of Estrogen on Cell Homeostasis and Remodeling With Special Focus on Cardiac Ischemia/Reperfusion Injury

“…In these cells ERα and ERβ appear as localized at the level of caveolae where a direct binding to striatin is essential for their membrane localization (65). Also GPER was detected in numerous cardiac compartments of the human heart (66) and in coronary artery VSMCs (67). During myocardial hypoxia due to infarction, GPER seems to be upregulated in cardiomyocytes (68).…”

Female Heart Health: Is GPER the Missing Link?

“…GPER binds estradiol (E 2 ) at a similar nanomolar affinity as ERα and ERβ and exerts comparable actions on calcium mobilization and phosphoinositide 3-kinase activation (45). ERα and GPER are expressed at similar levels in cardiac tissue from male and female rodents (46) as well as from humans (47). In contrast, reports of ERβ expression in the heart are conflicting, with ERβ mRNA detected in human cardiac tissue (48) but remaining below detectable levels in rodent cardiac tissue (46,49).…”

Modulation of the cardiac sodium/bicarbonate cotransporter by the renin angiotensin aldosterone system: pathophysiological consequences

“…Interestingly, Gros et al have demonstrated that aldosterone mediates its rapid effects in vascular endothelial cells through GPR30 activation (Gros et al, 2013). Moreover, it was reported that GPR30 is expressed in the heart (Bopassa et al, 2010) and that the stimulation of this receptor by estradiol (Patel et al, 2010) or G1, a specific GPR30 agonist, (Deschamps and Murphy, 2009; Bopassa et al, 2010) mediates protection during ischemia-reperfusion injury (Deschamps et al, 2010). Whether the potential effect of aldosterone on cardiac NBC could be mediated through MR or GPR30 activation represents an interesting issue that deserves future investigation.…”