Vascular effects of aldosterone: Sorting out the receptors and the ligands

Feldman, Ross D.; Gros, Robert

doi:10.1111/1440-1681.12157

Cited by 31 publications

(21 citation statements)

References 66 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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“…Furthermore, low doses of aldosterone have been shown to exert direct effects on the vascular system by inducing oxidative stress, inflammation, hypertrophic remodeling, fibrosis and endothelial dysfunction, demonstrating that activation of the MR pathway by the ligand or the receptor activate different pathogenic mechanisms (Briet and Schiffrin, 2013;Feldman and Gros, 2013;McCurley and Jaffe, 2012). Following injury of vessels, MR activation has been shown to promote smooth muscle cells fibrosis via the activation of the Placental Growth Factor (PGF)/VEGF Receptor 1 (VEGFR1) Fig.…”

Section: Cscr: the Mineralocorticoid Pathway Hypothesismentioning

confidence: 99%

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis

Daruich

Matet

Dirani

et al. 2015

Progress in Retinal and Eye Research

800

996

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Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress.

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“…on vascular smooth muscle contractility, cardiac fibrosis, cardiac inotropy, and on growthand death-regulatory mechanisms. 2 Furthermore, beyond its direct transcriptional regulatory effects, aldosterone has been shown to trigger the activation of several second messenger signaling pathways traditionally associated with the activation of membrane receptors including regulation of cAMP metabolism, intracellular calcium concentrations, tyrosine kinases (both receptor and nonreceptor), and mitogen-activated protein kinases, especially the extracellular signal-regulated kinases. 3 Studies during the last several years have elucidated the molecular mechanisms mediating at least some of these cardiovascular effects.…”

Section: Mechanisms Of Effectmentioning

confidence: 99%

Aldosterone and Blood Pressure Regulation

Feldman

2014

Hypertension

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T he purpose of this brief review is to highlight 3 recent conceptual advances in the ongoing exploration of the biology of aldosterone and how disorders of aldosterone metabolism and action lead to hypertension. Notably, important contributions to the advancement of our understanding in all 3 areas were published within the pages of Hypertension.For >60 years, the link between aldosterone and hypertension has remained a key focus of research. The focus on this hormone and how it regulates blood pressure (BP) date back to a period of time when its putative existence, separate from that of glucocorticoids, was only speculated. The research intensity in the field accelerated with the initial report of the isolation of aldosterone (originally named electrocortin) 1 in the early 1950s and the identification of its critical role in mediating the effects of activation of the renin-angiotensin system. Since then we have seen a continuously accelerating trajectory of research intensity.Advances in our understanding of the biology and pathobiology of aldosterone have been critical to our understanding of the mechanisms of hypertension and its management. A PubMed search of this connection between hypertension and aldosterone demonstrates its ongoing importance. For listings through September 2013, the search strategy (hypertension OR blood pressure AND aldosterone OR mineralocorticoid) returned 18 514 references dating from 1948. Notably >10% of those reports (2031) have been published during the past 3 years, a testament to the ongoing importance of this area of research.From this quantitatively and qualitatively impressive body of scholarship, I have identified 3 themes that I believe represent significant advances in our understanding of the link aldosterone and hypertension taken from studies published during the past 3 years in Hypertension and in other high impact journals. They are the following:1. Emerging concepts related to the mechanisms by which aldosterone mediates its cardiovascular effects, especially those acting through rapid pathways 2. New insights into the mechanisms of aldosterone secretion, which impact on hyperaldosteronism syndromes 3. Advances in the management of resistant hypertension as they relate to aldosterone inhibition. The Cardiovascular Actions of Aldosterone: Unappreciated Actions, Unappreciated Mechanisms of EffectUntil recently, the role of aldosterone in cardiovascular regulation and its mechanism of action in BP control were thought to be restricted to its renal effects. Aldosterone was widely seen as a hormone whose actions were predominantly related to renal sodium regulation and whose main mechanism of action was thought to be via regulation of transcription. However, during the past decade, important extrarenal, cardiovascular actions of aldosterone have been reported, viz. on vascular smooth muscle contractility, cardiac fibrosis, cardiac inotropy, and on growthand death-regulatory mechanisms. 2 Furthermore, beyond its direct transcriptional regulatory effects, aldosterone has...

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Vascular effects of aldosterone: Sorting out the receptors and the ligands

Cited by 31 publications

References 66 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

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis

Aldosterone and Blood Pressure Regulation

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