Evidence That the G Protein–Coupled Membrane Receptor GPR30 Contributes to the Cardiovascular Actions of Estrogen

Lindsey, Sarah H.; Chappell, Mark C.

doi:10.1016/j.genm.2011.10.004

Cited by 35 publications

(21 citation statements)

References 83 publications

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“…[27][28][29][30][31] However, the importance of GPER in regulation of lipoprotein metabolism in humans has been unexplored to date. Using a combination of human genetics and functional cellular biology, we found that the relatively common missense GPER P16L had a significant influence on LDL cholesterol concentrations.…”

Section: Discussionmentioning

confidence: 99%

G-Protein Estrogen Receptor as a Regulator of Low-Density Lipoprotein Cholesterol Metabolism

Hussain

Ding

Connelly

et al. 2015

ATVB

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T he importance of estrogen as a regulator of plasma lipid metabolism has been most clearly demonstrated in settings of estrogen deficiency (eg, menopause). Bilateral ovariectomy in premenopausal women causes an increase in plasma levels of low-density lipoprotein (LDL) when compared with premenopausal women with preserved ovaries.1 Furthermore, LDL cholesterol levels increase after onset of menopause. 2Multiple mechanisms have been proposed by which estrogens regulate lipoprotein metabolism in humans, including induction of hepatic LDL receptor expression, 3,4 reduction of hepatic secretion of acyl-coenzyme A: cholesterol acyltransferase 2-derived cholesteryl esters in plasma lipoproteins, 5 reduction of hepatic lipase, 6 and reduction of levels of proprotein convertase subtilisin kexin type 9 (PCSK9), 7 a key regulator of LDL receptor metabolism. 8 The receptor(s) mediating estrogen's effects on LDL metabolism is unclear. Estrogen's effects are triggered via 2 main receptor types. Classic estrogen receptors (ERs) have been shown to have both nuclear and cytoplasmic/membraneassociated sites of effect.9,10 More recently, a G-proteincoupled receptor, G-protein ER (GPER; aka GPR30) has been shown to mediate some of the so-called rapid (nongenomic) effects of estrogen. 11 We have recently shown that GPER is also activated by aldosterone. Objective-Estrogen deficiency is linked with increased low-density lipoprotein (LDL) cholesterol. The hormone receptor mediating this effect is unknown. G-protein estrogen receptor (GPER) is a recently recognized G-protein-coupled receptor that is activated by estrogens. We recently identified a common hypofunctional missense variant of GPER, namely P16L. However, the role of GPER in LDL metabolism is unknown. Therefore, we examined the association of the P16L genotype with plasma LDL cholesterol level. Furthermore, we studied the role of GPER in regulating expression of the LDL receptor and proprotein convertase subtilisin kexin type 9. Approach and Results-Our discovery cohort was a genetically isolated population of Northern European descent, and our validation cohort consisted of normal, healthy women aged 18 to 56 years from London, Ontario. In addition, we examined the effect of GPER on the regulation of proprotein convertase subtilisin kexin type 9 and LDL receptor expression by the treatment with the GPER agonist, G1. In the discovery cohort, GPER P16L genotype was associated with a significant increase in LDL cholesterol (mean±SEM): 3.18±0.05, 3.25±0.08, and 4.25±0.33 mmol/L, respectively, in subjects with CC (homozygous for P16), CT (heterozygotes), and TT (homozygous for L16) genotypes (P<0.05). In the validation cohort (n=339), the GPER P16L genotype was associated with a similar increase in LDL cholesterol: 2.17±0.05, 2.34±0.06, and 2.42±0.16 mmol/L, respectively, in subjects with CC, CT, and TT genotypes (P<0.05). In the human hepatic carcinoma cell line, the GPER agonist, G1, mediated a concentration-dependent increase in LDL receptor expression, blocked by eith...

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Section: Discussionmentioning

confidence: 99%

G-Protein Estrogen Receptor as a Regulator of Low-Density Lipoprotein Cholesterol Metabolism

Hussain

Ding

Connelly

et al. 2015

ATVB

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“…G-1 action through GPER mimics many of the actions of E2 in regulating vascular tone and providing protection from myocardial ischemia/reperfusion injury (Lindsey and Chappell, 2011;Meyer et al, 2011b;Han et al, 2013;Holm and Nilsson, 2013;Chakrabarti et al, 2014;Prossnitz and Barton, 2014). G-1-mediated GPER activation results in endothelial NO-mediated vasodilation in multiple vessels (Meyer et al, 2011b;Li et al, 2012;Lindsey et al, 2014), although a role for cAMP production in vascular smooth muscle cells has recently been identified (Lindsey et al, 2014).…”

Section: E Cardiovascular Systemmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

2015

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“…Membrane localization of GPER provides a novel mechanism for rapid, nongenomic responses to estrogen (27,60). Evidence that GPER plays an important role in mediating important cardiovascular actions of estrogen is building (24,40,47,49). GPER activation relaxes rat carotid (9), rat aorta (41), human mammary arteries (23), and coronary arteries (45,74) with or without endothelium, indicating that GPER acts directly on vascular smooth muscle to regulate vascular tone.…”

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confidence: 99%

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

Klussmann

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Yu X, Li F, Klussmann E, Stallone JN, Han G. G proteincoupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP. Am J Physiol Endocrinol Metab 307: E398 -E407, 2014. First published July 8, 2014 doi:10.1152/ajpendo.00534.2013.-Activation of GPER exerts a protective effect in hypertension and ischemia-reperfusion models and relaxes arteries in vitro. However, our understanding of the mechanisms of GPER-mediated vascular regulation is far from complete. In the current study, we tested the hypothesis that GPER-induced relaxation of porcine coronary arteries is mediated via cAMP/PKA signaling. Our findings revealed that vascular relaxation to the selective GPER agonist G-1 (0.3-3 M) was associated with increased cAMP production in a concentration-dependent manner. Furthermore, inhibition of adenylyl cyclase (AC) with SQ-22536 (100 M) or of PKA activity with either Rp-8-CPT-cAMPS (5 M) or PKI (5 M) attenuated G-1-induced relaxation of coronary arteries preconstricted with PGF2␣ (1 M). G-1 also increased PKA activity in cultured coronary artery smooth muscle cells (SMCs). To determine downstream signals of the cAMP/PKA cascade, we measured RhoA activity in cultured human and porcine coronary SMCs and myosin-light chain phosphatase (MLCP) activity in these artery rings by immunoblot analysis of phosphorylation of myosin-targeting subunit protein-1 (p-MYPT-1; the MLCP regulatory subunit). G-1 decreased PGF2␣-induced p-MYPT-1, whereas Rp-8-CPT-cAMPS prevented this inhibitory effect of G-1. Similarly, G-1 inhibited PGF2␣-induced phosphorylation of MLC in coronary SMCs, and this inhibitory effect was also reversed by Rp-8-CPT-cAMPS. RhoA activity was downregulated by G-1, whereas G36 (GPER antagonist) restored RhoA activity. Finally, FMP-API-1 (100 M), an inhibitor of the interaction between PKA and A-kinase anchoring proteins (AKAPs), attenuated the effect of G-1 on coronary artery relaxation and p-MYPT-1. These findings demonstrate that localized cAMP/PKA signaling is involved in GPER-mediated coronary vasodilation by activating MLCP via inhibition of RhoA pathway.

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Evidence That the G Protein–Coupled Membrane Receptor GPR30 Contributes to the Cardiovascular Actions of Estrogen

Cited by 35 publications

References 83 publications

G-Protein Estrogen Receptor as a Regulator of Low-Density Lipoprotein Cholesterol Metabolism

G-Protein Estrogen Receptor as a Regulator of Low-Density Lipoprotein Cholesterol Metabolism

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

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