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ATHEROSCLEROSIS / EXPERIMENTAL RESEARCH
G protein-coupled estrogen receptor GPR30 exerts vasoprotective effects in apolipoprotein E-deficient mice
1
Department of Internal Medicine II, Cardiology, Pneumology, Angiology, University Hospital Bonn, Bonn, Germany
Submission date: 2020-01-30
Final revision date: 2020-08-15
Acceptance date: 2020-09-02
Online publication date: 2021-05-03
Corresponding author
Julian Jehle
Venusberg-Campus 1 Building 13 53127 Bonn, Germany Phone: +49 228 287 51484 Fax: +49 228 287 51482
Venusberg-Campus 1 Building 13 53127 Bonn, Germany Phone: +49 228 287 51484 Fax: +49 228 287 51482
KEYWORDS
G-1G protein-coupled receptor 30atherosclerosisglucose tolerancereactive oxygen speciesangiotensin II type 1 receptor
TOPICS
ABSTRACT
Introduction:
GPR30 is an intracellular transmembrane G protein-coupled receptor that mediates non-genomic estrogen signaling. The GPR30 agonist G-1 modulates glucose homeostasis and vascular function. However, its impact on vascular inflammation and atherogenesis has not yet been investigated in the atherosclerotic apolipoprotein E-deficient (ApoE-/-) mouse model.
Material and methods:
ApoE-/- mice were fed a high-cholesterol diet for 7 weeks while being treated with the selective GPR30 agonist G-1 (n = 6–7 per sex and treatment group). After the treatment period, vascular relaxation capacity, vascular oxidative stress, and atherosclerotic plaque burden were assessed. In vitro, reactive oxygen species, expression levels of the angiotensin II type 1 (AT1) receptor, and the proliferation rate were quantified in human coronary artery smooth muscle cells (HCASMC).
Results:
G-1 significantly improved glucose tolerance in vivo (142.2 ±8.1 mg/dl vs. 204.6 ±13.3 mg/dl), reduced vascular oxidative stress (221 ±88 RLU/s/mg vs. 1,983 ±885 RLU/s/mg), and improved endothelium-dependent vasodilation (relaxation to 35.1 ±4.5% vs. 63.0 ±4.6%). Furthermore, treatment with G-1 significantly reduced the atherosclerotic plaque burden of female ApoE-/- mice (56.5 ±3.7% vs. 75.5 ±2.9%). In vitro, G-1 significantly downregulated the AT1 receptor in HCASMC (0.67 ±0.09-fold). Furthermore, G-1 blunted angiotensin II-induced ROS production in HCASMC (817 ±7 RLU/s/mg vs. 1,625 ±105 RLU/s/mg) and diminished HCASMC proliferation (–26.8 ±2.7% vs. +50.4 ±1.7%).
Conclusions:
Selective GPR30 activation improves glucose tolerance in vivo and decreases vascular ROS production in vitro and in vivo. In vitro, the antioxidant effect might be mediated by downregulation of the AT1 receptor. In vivo, the antioxidant effect of G-1 is associated with improved endothelial function and reduced atherosclerotic plaque burden in ApoE-deficient mice, indicating beneficial vascular effects of GPR30 activation. GPR30 agonism may therefore represent a promising therapeutic strategy against atherosclerosis.
GPR30 is an intracellular transmembrane G protein-coupled receptor that mediates non-genomic estrogen signaling. The GPR30 agonist G-1 modulates glucose homeostasis and vascular function. However, its impact on vascular inflammation and atherogenesis has not yet been investigated in the atherosclerotic apolipoprotein E-deficient (ApoE-/-) mouse model.
Material and methods:
ApoE-/- mice were fed a high-cholesterol diet for 7 weeks while being treated with the selective GPR30 agonist G-1 (n = 6–7 per sex and treatment group). After the treatment period, vascular relaxation capacity, vascular oxidative stress, and atherosclerotic plaque burden were assessed. In vitro, reactive oxygen species, expression levels of the angiotensin II type 1 (AT1) receptor, and the proliferation rate were quantified in human coronary artery smooth muscle cells (HCASMC).
Results:
G-1 significantly improved glucose tolerance in vivo (142.2 ±8.1 mg/dl vs. 204.6 ±13.3 mg/dl), reduced vascular oxidative stress (221 ±88 RLU/s/mg vs. 1,983 ±885 RLU/s/mg), and improved endothelium-dependent vasodilation (relaxation to 35.1 ±4.5% vs. 63.0 ±4.6%). Furthermore, treatment with G-1 significantly reduced the atherosclerotic plaque burden of female ApoE-/- mice (56.5 ±3.7% vs. 75.5 ±2.9%). In vitro, G-1 significantly downregulated the AT1 receptor in HCASMC (0.67 ±0.09-fold). Furthermore, G-1 blunted angiotensin II-induced ROS production in HCASMC (817 ±7 RLU/s/mg vs. 1,625 ±105 RLU/s/mg) and diminished HCASMC proliferation (–26.8 ±2.7% vs. +50.4 ±1.7%).
Conclusions:
Selective GPR30 activation improves glucose tolerance in vivo and decreases vascular ROS production in vitro and in vivo. In vitro, the antioxidant effect might be mediated by downregulation of the AT1 receptor. In vivo, the antioxidant effect of G-1 is associated with improved endothelial function and reduced atherosclerotic plaque burden in ApoE-deficient mice, indicating beneficial vascular effects of GPR30 activation. GPR30 agonism may therefore represent a promising therapeutic strategy against atherosclerosis.
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