Endothelin receptors: what's new and what do we need to know?

Watts, Stephanie W.

doi:10.1152/ajpregu.00584.2009

Cited by 69 publications

(60 citation statements)

References 120 publications

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“…34 The ET A receptor belongs to G protein-coupled receptors, and its downstream signals require Gq. 35 Data from the present study suggest that estradiol-mediated protective stress-kinase programs modulated induction of the maladaptive calcineurin pathway, which was responsible for a mild and adaptive cardiac phenotype in female mice with intact ER␤. In vitro data, in which the antihypertrophic effect of an ER␤ agonist was similar to that of estradiol in ET-1-stimulated female mouse cardiomyocytes, were consistent with this idea.…”

Section: Discussionmentioning

confidence: 59%

Estrogen Receptor-β Signals Left Ventricular Hypertrophy Sex Differences in Normotensive Deoxycorticosterone Acetate-Salt Mice

et al. 2011

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Abstract-We found earlier that deoxycorticosterone acetate-salt treatment causes blood pressure-independent left ventricular hypertrophy, but only in male mice. To test the hypothesis that the estrogen receptor-␤ (ER␤) protects the females from left ventricular hypertrophy, we treated male and female ER␤-deficient (ER␤ Ϫ/Ϫ ) mice and their male and female littermates (wild-type [WT]) with deoxycorticosterone acetate-salt and made them telemetrically normotensive with hydralazine. WT males had increased (ϩ16%) heart weight/tibia length ratios compared with WT females (ϩ7%) at 6 weeks. In ER␤ Ϫ/Ϫ mice, this situation was reversed. Female WT mice had the greatest heart weight/tibia length ratio increases of all of the groups (ϩ23%), even greater than ER␤ Ϫ/Ϫ males (ϩ10%). Echocardiography revealed concentric left ventricular hypertrophy in male WT mice, whereas ER␤ Ϫ/Ϫ females developed dilative left ventricular hypertrophy. The hypertrophic response in female ER␤ Ϫ/Ϫ mice was accompanied by the highest degree of collagen deposition, indicating maladaptive remodeling. ER␤ ϩ/ϩ females showed robust protective p38 and extracellular signal-regulated kinase 1/2 signaling relationships compared with other groups. Calcineurin A␤ expression and its positive regulator myocyte-enriched calcineurin-interacting protein 1 were increased in deoxycorticosterone acetate-salt female ER␤ Ϫ/Ϫ mice, yet lower than in WT males. Endothelin increased murine cardiomyocyte hypertrophy in vitro, which could be blocked by estradiol and an ER␤ agonist. We conclude that a functional ER␤ is essential for inducing adaptive p38 and extracellular signal-regulated kinase signaling, while reducing maladaptive calcineurin signaling in normotensive deoxycorticosterone acetate female mice. Our findings address the possibility of sex-specific cardiovascular therapies. Key Words: estrogen receptor-␤, heart Ⅲ hypertrophy Ⅲ fibrosis Ⅲ calcineurin Ⅲ p38 MAPK Ⅲ ERK1/2 F emales seem to be relatively protected from cardiovascular disease on the basis of animal and human studies; estrogens could play a role. 1-3 Clinical trials using estrogens for improving cardiovascular health were disappointing, perhaps because of poor estrogen receptor (ER) isoform selectivity and specificity. 4 The 2 functional isoforms, ER␣ and ER␤, are expressed in the myocardium. 5 Receptor-mediated effects of estrogens on cardiomyocyte biology are injury or stimulus dependent, 4,6 which, in turn, implicates activation of distinct, sex-dependent, signaling pathways and gene expression programs. 7 We described recently a sex-specific dimorphism in cardiac adaptation in response to deoxycorticosterone acetate (DOCA)-salt and showed that this response was independent of blood pressure. 8 Male mice developed left ventricular hypertrophy (LVH) that was linked to activation of a calcineurin-dependent pathway, which increased proinflammatory and profibrotic responses. In contrast, female DOCA mice maintained their initial physiological adaptive cardiac phenotype despite mineralocorticoid and...

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Section: Discussionmentioning

confidence: 59%

Estrogen Receptor-β Signals Left Ventricular Hypertrophy Sex Differences in Normotensive Deoxycorticosterone Acetate-Salt Mice

et al. 2011

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“…Novel aspects on ET receptor pharmacology can be found in two very elegant articles by Dr. Stephanie Watts (166) and Dr. Erika Boesen (11). These authors focused on the interactions between ET receptors (formation of heterodimers and homodimers, which may explain some puzzling results from receptor-binding and functional studies) (11,166), the possibility of differential signaling or biased agonists (that different agonists can elicit different signal transduction events through the same receptor), and interactions of components of the ET system with other molecules, e.g., the dual angiotensin II-ET receptor and the Parkinassociated ET receptor-like receptor (where the ET receptor B-like protein receptor 1 functions as a substrate for Parkin, a polypeptide with similarities to ubiquitin protein ligase E3) (166).…”

Section: (Signaling Pathways Activated By Et-1 That Can Be Modified Bmentioning

confidence: 99%

“…They will be referred to excellent reviews on O-GlcNAcylation (54,55,63,84,90,110,167,169,177). Detailed information on ET peptides, ET receptors, ET signaling, models for the study of ET in disease conditions, and development and therapeutic use of ET A /ET B receptor antagonists can be found on excellent and more comprehensive reviews on these specific topics (6,8,11,12,30,31,34,37,67,79,81,115,122,131,141,142,154,160,166).…”

mentioning

confidence: 99%

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Lima

Giachini

Hardy

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Glycosylation with Olinked ␤-N-acetylglucosamine (O-GlcNAc) or O-GlcNAcylation on serine and threonine residues of nuclear and cytoplasmic proteins is a posttranslational modification that alters the function of numerous proteins important in vascular function, including kinases, phosphatases, transcription factors, and cytoskeletal proteins. O-GlcNAcylation is an innovative way to think about vascular signaling events both in physiological conditions and in disease states. This posttranslational modification interferes with vascular processes, mainly vascular reactivity, in conditions where endothelin-1 (ET-1) levels are augmented (e.g. salt-sensitive hypertension, ischemia/reperfusion, and stroke). ET-1 plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions. Recognition of ET-1 by the ET A and ETB receptors activates intracellular signaling pathways and cascades that result in rapid and long-term alterations in vascular activity and function. Components of these ET-1-activated signaling pathways (e.g., mitogen-activated protein kinases, protein kinase C, RhoA/Rho kinase) are also targets for O-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activates O-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified by O-GlcNAcylation. A brief description of the O-GlcNAcylation biology is presented, and its role on vascular function is addressed. ET-1-induced O-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay between O-GlcNAcylation and O-phosphorylation is addressed. endothelin receptor; vascular signaling; O-GlcNAc modification GLYCOSYLATION IS THE SITE-specific enzymatic addition of saccharides to proteins and lipids. There are many types of glycosylation, but great interest has been directed to O-GlcNAcylation, or glycosylation with O-linked ␤-N-acetylglucosamine or ␤-Olinked 2-acetamido-2-deoxy-D-glycopyranose (54,55,169). In this unusual form of protein glycosylation, a single sugar [␤-N-acetylglucosamine (O-GlcNAc)] is added to serine and threonine residues of nuclear or cytoplasmic proteins (54,55,169).Considering that almost every functional class of proteins is subject to O-GlcNAcylation (55, 177), this specific posttranslational modification has been implicated in several biological functions, including transcription or translation, stress responses, and energy metabolism. Proteins with an important role in vascular function are also targets for O-GlcNAcylation. Examples include endothelial nitric oxide (NO) synthase (eNOS), sarcoplasmic reticulum calcium (Ca 2ϩ )-ATPase (SERCA), phospholipase C (PLC), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), and proteins involved in cytoskeleton regulation and microtubule assembly (22,55,177), indicating that this posttranslational modification may play an important role in vascular (...

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“…50 Once ET-1 binds to its receptor (Gq-proteins) on the vascular smooth muscle it induces an increase in inositol 1,4,5-triphosphate levels, with subsequent calcium release and muscle contraction. 50 Specifically, it has been shown that EC dysfunction and inflammation contribute to an overproduction of ET-1 in humans. 52 The exact role of ET-1 in VTE, however, remains unclear.…”

Section: Platelet-activating Factormentioning

confidence: 99%

Inflammation and Acute Venous Thrombosis

Díaz¹

2011

Oncology &Amp; Hematology Review (US)

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Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE occurs worldwide, and in all age groups and socioeconomic populations in North America and western Europe.1,2 In a recent study by Heit et al., the estimated total annual cases of VTE occurring in the US exceeded 900,000, of which more than 250,000 were fatal. 3 Despite progress in medicine and biology, no changes in the incidence of VTE were noted during the 25-year cohort study. InflammationInflammation is a complex, highly regulated biological process that can be triggered by several stimuli, such as pathogens, noxious mechanical and chemical agents, and autoimmune responses. 10 In the clinical setting, inflammation is described as redness and swelling with heat and pain. Biologically, these signs and symptoms are explained by an increasing microvascular caliber, enhanced vascular permeability, leukocyte recruitment, and the release of inflammatory mediators. 10Inflammation in physiologic states is a controlled response that protects against further injury and clears damaged tissue. In disease states such as sepsis, however, uncontrolled inflammation can lead to a marked breakdown of the extracellular matrix as well as organ destruction. 10Inflammation can also be acute or chronic-two well-characterized states in which neutrophils and monocytes, respectively, play an important role. Similarly, DVT is a process with acute and chronic phases. In this setting, the main cells observed during acute DVT are the neutrophils.Monocytes are observed during the chronic phase. This parallel between inflammation and DVT is highly suggestive of a relationship. Inflammation and Vein Thrombosis Endothelial CellsECs play a pivotal role in venous thrombosis in healthy individuals. While arterial thrombosis requires EC disruption with collagen exposure (as Inflammation and Acute Venous ThrombosisJose Antonio Diaz, MD published material that assesses the relationship between inflammation and acute vein thrombosis. The article will focus on the role of endothelial cells, leukocytes, platelets, and microparticles in acute vein thrombosis and discuss the role of thrombin, P-selectin, platelet-activating factor, endothelin-1, and nitric oxide from the perspective of inflammation.

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Endothelin receptors: what's new and what do we need to know?

Cited by 69 publications

References 120 publications

Estrogen Receptor-β Signals Left Ventricular Hypertrophy Sex Differences in Normotensive Deoxycorticosterone Acetate-Salt Mice

Estrogen Receptor-β Signals Left Ventricular Hypertrophy Sex Differences in Normotensive Deoxycorticosterone Acetate-Salt Mice

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Inflammation and Acute Venous Thrombosis

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