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Gene & Protein in Disease GPER1 in brain and heart diseases

a member of the RAMP family of single-transmembrane The peroxisome proliferator-activated receptor delta is
proteins, interacts with GPER1 and is transcriptionally a key player in the metabolic function of the heart. A recent
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upregulated by E2. In HEK293 cells, cotransfection of study demonstrated that GPER1 can promote the nuclear
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RAMP3 and GPER1 could increase RAMP3 expression translocation of peroxisome proliferator-activated receptor
at the plasma membrane. In vivo GPER1 activation by delta, thereby mitigating oxidative stress and apoptosis
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the administration of G-1 in RAMP3 WT and RAMP3 during sepsis. Therefore, modulation of GPER1 through
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KO mice for 40 days led to a sex-dependent reduction in the action of interaction partners such as RAMP3 or
the left ventricular hypertrophy and perivascular fibrosis inhibition or activation of kinases further downstream
in RAMP3 WT male mice but not in RAMP3 KO male or of GPER1-activated signaling pathways might represent
female mice. Furthermore, another study showed that promising targets for treating heart failure (Figure 2). 255
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RAMP3 plays a sex-dependent role in cardiac hypertrophy
and heart failure by affecting only male RAMP3 KO mice 3.3. Atrial fibrillation (AF)
through increased activation of Akt signaling with no effect AF is the most common tachycardic arrhythmia, which is
on female mice. Modification of the RAMP3–GPER1 associated with increased mortality as well as poor quality of
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interaction and its associated intracellular pathways could life. It causes a five-fold increase in the risk of developing
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help identify novel pharmacological targets for drugs stroke and heart failure and a two-fold increase in the risk
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against cardiac pathophysiological mechanisms, especially of developing myocardial infarction and coronary heart
in male patients. disease, especially in women. In contrast, in a Taiwanese
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Another study investigated the cardioprotective cohort study, Chao et al. reported a higher risk of developing
effect of GPER1 in male rat hearts with regard to the myocardial infarction in men with AF than in women
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translocation of PKC. PKC activates the mitogen- with AF. An important interaction and dependency
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activated protein kinase kinase 2 (MAPK2)/ERK1/2 exist between several cardiac pathomechanisms, such as
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signaling pathway and further phosphorylates glycogen the association between hypertension and AF. Atrial
synthase kinase 3 (GSK3) β in reperfusion injury. The remodeling plays a key role in AF development, and histone
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late onset of reperfusion after a period of ischemia causes deacetylases (HDACs) are associated with AF initiation.
apoptosis of the cardiac tissue. Activation of GPER1 Sawa et al. demonstrated in an in vivo mouse model that
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exerts a cardioprotective effect in H9C2 myocardial cells HDAC6 activation induced AF; in this case, HDAC6 was
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after ischemia-reperfusion injury by inhibiting cardiac activated by chronic hypertension. Moreover, Zhao
apoptosis. There is extensive evidence showing that et al. showed the involvement of GPER1 in the inhibition
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inflammatory processes are critically involved, especially of HDAC4 in cardiomyocytes obtained from female
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in reperfusion injury. Using cardiomyocyte-specific OVX mice. In particular, the risk of developing AF is
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GPER1 KO mice, Wang et al. demonstrated GPER1- higher in menopausal women than in premenopausal
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mediated downregulation of the NLRP3 inflammasome women. Liu et al. demonstrated that GPER1 activation
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(section 2.1), which contains, for instance, NLRP3, caspase reduces atrial fibrosis induced by AT II in an OVX mouse
1, IL-1β, and IL-18 that represent inflammatory substances model. They proposed a G-1-induced reduction of atrial
that could contribute to heart failure. 246,247 Doxorubicin, a remodeling, which prevented AF-induced mortality after
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drug used in cancer therapy, is often associated with the receptor activation. In addition, estrogen monotherapy
side effect of cardiotoxicity. Activation of GPER1 could considerably reduces AF and mortality rates in menopausal
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mitigate the adverse effects of doxorubicin therapy by women, besides exerting additional cardioprotective
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reducing the levels of inflammatory mediators such as effects. In conclusion, GPER1 and its specific activation
TNF. Consistent with this, the cardiomyocyte-specific through its agonist G-1 provide a possible basis for
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KO of GPER1 in male mice resulted in a gene enrichment antiarrhythmic therapy through the downregulation of
of inflammatory genes, whereas this effect was not HDACs (Figure 2), although there are currently no data
observed in female GPER1 KO mice. KO of GPER1 in on these possible beneficial effects and the involvement of
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female mice results in the left ventricular dysfunction as HDACs in human cardiac tissue.
well as an upregulation of oxidative stress-related genes. 4. Conclusion
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Based on animal and human studies, it is known that
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oxidative stress is elevated in males compared with that in There has been an increase in the number of studies on
females. A possible cellular mechanism is the opening of GPER1 and its involvement in the regulation of various
the mitochondrial permeability transition pore resulting molecular mechanisms causing alterations at cellular
in cell death that could be antagonized by the activation and organism levels over the past few decades, and
of GPER1. 253 GPER1 has become an integral component of current
Volume 4 Issue 1 (2025) 15 doi: 10.36922/gpd.4632