GPER Mediates Cardiotropic Effects in Spontaneously Hypertensive Rat Hearts

Abstract

Estrogens promote beneficial effects in the cardiovascular system mainly through the estrogen receptor (ER)α and ERβ, which act as ligand-gated transcription factors. Recently, the G protein-coupled estrogen receptor (GPER) has been implicated in the estrogenic signaling in diverse tissues, including the cardiovascular system. In this study, we demonstrate that left ventricles of male Spontaneously Hypertensive Rats (SHR) express higher levels of GPER compared to normotensive Wistar Kyoto (WKY) rats. In addition, we show that the selective GPER agonist G-1 induces negative inotropic and lusitropic effects to a higher extent in isolated and Langendorff perfused hearts of male SHR compared to WKY rats. These cardiotropic effects elicited by G-1 involved the GPER/eNOS transduction signaling, as determined by using the GPER antagonist G15 and the eNOS inhibitor L-NIO. Similarly, the G-1 induced activation of ERK1/2, AKT, GSK3β, c-Jun and eNOS was abrogated by G15, while L-NIO prevented only the eNOS phosphorylation. In hypoxic Langendorff perfused WKY rat heart preparations, we also found an increased expression of GPER along with that of the hypoxic mediator HIF-1α and the fibrotic marker CTGF. Interestingly, G15 and L-NIO prevented the ability of G-1 to down-regulate the expression of both HIF-1α and CTGF, which were found expressed to a higher extent in SHR compared to WKY rat hearts. Collectively, the present study provides novel data into the potential role played by GPER in hypertensive disease on the basis of its involvement in myocardial inotropism and lusitropism as well as the expression of the apoptotic HIF-1α and fibrotic CTGF factors. Hence, GPER may be considered as a useful target in the treatment of some cardiac dysfunctions associated with stressful conditions like the essential hypertension.

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

“…In addition, our and other studies have largely demonstrated the involvement of GPER in the stimulatory effects elicited by estrogens in cancer cells and tumor microenvironment (6,(9)(10)(11). Significantly, several studies performed in different cell and animal models have ascertained the role exerted by GPER in certain pathological conditions characterized by oxygen deficiency (30,31,(74)(75)(76)(77)(78). In this regard, it has been demonstrated that GPER activation may decrease myocardial damage and increase functional recovery after ischemia-reperfusion (I/R) injury, which often induces dangerous complications like arrhythmia in patients with myocardial infarction (74)(75)(76)(77)(78).…”

“…Likewise, in rat hearts of both sexes exposed to I/R injury, the activation of GPER reduced myocardial inflammation and infarct size as well as improved immunosuppression and myocardial mechanical performance (79)(80)(81). Interestingly, the expression levels of both GPER and HIF-1α were found to be increased in spontaneously hypertensive rat hearts compared to normotensive controls, suggesting that HIF-1α/ GPER signaling may represent a transduction mediator in certain conditions characterized by elevated blood pressure (74), which is tightly linked to hypoxia (82). Of note, the selective GPER agonist G-1 markedly lowered blood pressure in normotensive and hypertensive rats (83,84), thus supporting the hypothesis that GPER may be a valuable pharmacological target for the prevention/treatment of certain cardiovascular diseases.…”

“…Significantly, several studies performed in different cell and animal models have ascertained the role exerted by GPER in certain pathological conditions characterized by oxygen deficiency (30,31,(74)(75)(76)(77)(78). In this regard, it has been demonstrated that GPER activation may decrease myocardial damage and increase functional recovery after ischemia-reperfusion (I/R) injury, which often induces dangerous complications like arrhythmia in patients with myocardial infarction (74)(75)(76)(77)(78). Likewise, in rat hearts of both sexes exposed to I/R injury, the activation of GPER reduced myocardial inflammation and infarct size as well as improved immunosuppression and myocardial mechanical performance (79)(80)(81).…”

Activation of G protein-coupled estrogen receptor 1 (GPER-1) decreases fluid intake in female rats

“…The expression of GPER-1 in tissues associated with the cardiovascular system along with an increase in expression in hearts of spontaneously hypertensive rats suggests a role of GPER-1 in controlling cardiovascular tone (Bopassa et al, 2010; Broughton et al, 2010; De Francesco et al, 2013; Ding et al, 2009; Isensee et al, 2009). Indeed, female GPER-1 knockout mice are hypertensive (Martensson et al, 2009) and the hypotensive effect of pharmacological GPER-1 activation is lost in male and female GPER-1 knockout mice (Haas et al, 2009).…”

“…In this sense, the known effects of GPER-1 on the maintenance of cardiovascular homeostasis (De Francesco et al, 2013; Lindsey et al, 2009; Martensson et al, 2009) make it tempting to speculate that GPER-1 affects fluid intake, perhaps more proximally than any potential effects on food intake. For example, GPER-1 activation decreases mean arterial blood pressure in hypertensive OVX mRen2.Lewis rats (Lindsey et al, 2009).…”