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Gene & Protein in Disease GPER1 in brain and heart diseases

Figure 2. Role of GPER1 in cardiovascular diseases. Besides its involvement in neurological diseases, GPER1 plays a role in several molecular mechanisms
influencing the pathophysiology of cardiological diseases with sex-specific differences. Here, the impact of GPER1 on disorders of the cardiovascular
system is illustrated, with a favorable effect of GPER1 activation (green headlines) and a controversially discussed effect (yellow headlines) on the outcome
of the respective disease. Sex-specific differences in the positive effects of GPER1 activation are illustrated by different sizes of the symbols of the biological
sexes (same size: same effects in both sexes; outstanding female symbol: larger effect in females; and outstanding male symbol: larger effect in males)
Abbreviations: AT II: Angiotensin II; GPER1: G protein-coupled estrogen receptor; OVX: Ovariectomized.
but only an upregulation of inflammatory response genes hypertension induced by a high-fat diet in female rats.
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in male GPER1 KO mice compared with that in WT and In conclusion, different flavonoids as well as other
sex-matched animal groups. Regarding both sexes, phytoestrogens that activate GPER1 could be important
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exposure to the xenoestrogen BPA during childhood and for diverse clinical applications for cardiovascular diseases,
adulthood has been linked to a higher risk of developing although more specific research is required. Hypertrophy
cardiovascular diseases. Furthermore, children who have of the ventricle as a consequence of aortic hypertension
been exposed in utero to increased BPA levels, measured is a risk factor for arrhythmias, ischemia, and sudden
from maternal urinary concentrations at approximately death, because long-term cardiac hypertrophy results in
20 weeks of gestation, showed a significantly higher cardiac dilatation and heart failure. 231,232 Di Mattia et al.
diastolic blood pressure at age 4 years. BPA acts as an reported that activation of GPER1 with G-1 not only
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endocrine disruptor, and in high doses, it causes heart prevents hypertrophy but also regresses hypertrophy
malformations, whereas EGCG could rescue these in neonatal cardiac male rat myocytes. This GPER1-
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pathogenic effects during zebrafish heart development. dependent effect reduces pERK1/2 and stimulates the
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In an artificial aortic ring model and in silico studies, activation of Akt signaling. 233,234 Furthermore, angiotensin
Moreno-Ulloa et al. demonstrated that (-)-epicatechin, II (AT II)-induced hypertrophy can be antagonized by the
another flavanol with cardiovascular beneficial effects, activation of GPER1 through the regulation of PI3K/Akt/
can mediate vasodilatation through GPER1 activation mammalian target of rapamycin signaling. Activation
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similar to G-1, through activation of the kinase c-Src and of the PI3K/Akt pathway through E2 receptors also
cross-talk with EGFR. Phytoestrogens are considered reduces cardiomyocyte apoptosis in female mice. Sex-
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promising therapeutics for postmenopausal atherosclerotic specific protective effects have also been reported for the
cardiovascular diseases. In vivo as well as in vitro assays cAMP/L-type calcium channel pathway based on the
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by Feng et al. demonstrated the anti-inflammatory and observation of an increase in I density, contraction,
CaL
antiapoptotic effects of kaempferol, a naturally occurring and calcium transient amplitudes in isolated left ventricle
flavonoid, by the activation of GPER1 in blood vessels, apical myocytes in female and OVX E2-treated female
possibly attenuating atherosclerosis in postmenopausal mice compared with that in male and OVX female mice.
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women. In addition, Zhao et al. demonstrated Interestingly, Machuki et al. also reported that these
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improvement of cardiac hypertrophy by GPER1 activation beneficial effects of E2 could be abolished by pretreatment
through the flavonoid phytoestrogen icariin in OVX of myocytes obtained from OVX female mice with the
female mice, emphasizing the cardioprotective role of GPER1 antagonist G-15, whereas the ERα and ERβ
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GPER1. Other phytoestrogens such as the non-flavonoid antagonist ICI 182,780 did not cancel the positive effects of
polyphenol resveratrol have also been shown to prevent E2. The receptor activity-modifying protein 3 (RAMP3),
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Volume 4 Issue 1 (2025) 14 doi: 10.36922/gpd.4632