Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium

Pieske, Burkert; Beyermann, Beate; Breu, Volker; Löffler, Bernd–Michael; Schlotthauer, Klaus; Maier, Lars S.; Schmidt‐Schweda, Stephan; Just, Hanjörg; Hasenfuß, Gerd

doi:10.1161/01.cir.99.14.1802

Cited by 161 publications

(119 citation statements)

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“…6A and B). Both cell types displayed brief negative inotropic phases eventually leading to sustained positive inotropy, consistent with previous observations in various mammalian species [4,[37][38][39]. However, the location at which ET-1-mediated signal transduction occurs is evidently different between the two cell types.…”

Section: Discussionsupporting

confidence: 89%

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

et al. 2010

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a b s t r a c t Narrow, tubular, inward projections of the sarcolemma ('T-tubules') are an established feature of adult mammalian ventricular myocytes that enables them to generate the whole-cell Ca 2+ transients and produce coordinated contraction. Loss of T-tubules can occur during ageing and under pathological conditions, leading to altered cardiac excitation-contraction coupling. In contrast to adult ventricular cells, atrial myocytes do not generally express an extensive T-tubule system at any stage of development, and therefore rely on Ca 2+ channels around their periphery for the induction of Ca 2+ signalling and excitation-contraction coupling. Consequently, the characteristics of systolic Ca 2+ signals in adult ventricular and atrial myocytes are temporally and spatially distinct. However, although atrial myocytes do not have the same regularly spaced convoluted T-tubule structures as adult ventricular cells, it has been suggested that a proportion of adult atrial cells have a more rudimentary tubule system. We examined the structure and function of these atrial tubules, and explored their impact on the initiation and recovery of Ca 2+ signalling in electrically paced myocytes. The atrial responses were compared to those in adult ventricular cells that had intact T-tubules, or that had been chemically detubulated. We found that tubular structures were present in a significant minority of adult atrial myocytes, and were unlike the T-tubules in adult ventricular cells. In those cells where they were present, the atrial tubules significantly altered the on-set, amplitude, homogeneity and recovery of Ca 2+ transients. The properties of adult atrial myocyte Ca 2+ signals were different from those in adult ventricular cells, whether intact or detubulated. Excitation-contraction coupling in detubulated adult ventricular myocytes, therefore, does not approximate to atrial signalling, even though Ca 2+ signals are initiated in the periphery of the cells in both of these situations. Furthermore, inotropic responses to endothelin-1 were entirely dependent on T-tubules in adult ventricular myocytes, but not in atrial cells. Our data reveal that that the T-tubules in atrial cells impart significant functional properties, but loss of these tubular membranes does not affect Ca 2+ signalling as dramatically as detubulation in ventricular myocytes.

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Section: Discussionsupporting

confidence: 89%

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

et al. 2010

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“…There are at least 2 cardiac ET-1 receptors, ET A and ET B . 27,32,33 ET-1 exerts its inotropic and hypertrophic effects mainly through the activation of the G protein-coupled ET A receptors on cardiomyocytes. 32,33 In contrast, ET B receptors only mediate inotropic effects without having any effect on hypertrophy.…”

Section: Xu Et Al Et-1 and Ros In Leptin-induced Cardiac Hypertrophymentioning

confidence: 99%

“…27,32,33 ET-1 exerts its inotropic and hypertrophic effects mainly through the activation of the G protein-coupled ET A receptors on cardiomyocytes. 32,33 In contrast, ET B receptors only mediate inotropic effects without having any effect on hypertrophy. 32,33 In our present study, the results showed that leptin-induced ET-1 generation and treatment with ET A receptor antagonist ABT-627 significantly inhibited leptin-induced hypertrophy in cultured neonatal rat cardiomyocytes.…”

Section: Xu Et Al Et-1 and Ros In Leptin-induced Cardiac Hypertrophymentioning

confidence: 99%

“…32,33 In contrast, ET B receptors only mediate inotropic effects without having any effect on hypertrophy. 32,33 In our present study, the results showed that leptin-induced ET-1 generation and treatment with ET A receptor antagonist ABT-627 significantly inhibited leptin-induced hypertrophy in cultured neonatal rat cardiomyocytes. These data suggest that the ET-1-ET A pathway mediates leptin-induced hypertrophic effects in cultured neonatal rat cardiomyocytes.…”

Section: Xu Et Al Et-1 and Ros In Leptin-induced Cardiac Hypertrophymentioning

confidence: 99%

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Leptin Induces Hypertrophy via Endothelin-1–Reactive Oxygen Species Pathway in Cultured Neonatal Rat Cardiomyocytes

et al. 2004

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Background-Obesity is a major risk factor for the development of cardiovascular disease. Emerging evidence indicates that leptin, a protein encoded by the obesity gene, is linked with cardiac hypertrophy in obese humans and directly induces cardiomyocyte hypertrophy in vitro. However, the mechanisms by which leptin induces cardiomyocyte hypertrophy are poorly understood. Methods and Results-This study investigated how leptin contributes to cardiomyocyte hypertrophy. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of leptin on hypertrophy. Both endothelin-1 (ET-1) and reactive oxygen species (ROS) levels were elevated in a concentration-dependent manner in cardiomyocytes treated with leptin for 4 hours compared with those cells without leptin treatment. ET-1 stimulated ROS production in a concentrationdependent manner in cardiomyocytes. The augmentation of ROS levels in cardiomyocytes treated with both leptin and ET-1 was reversed by a selective ET A receptor antagonist, ABT-627, and catalase, a hydrogen peroxide-decomposing enzyme. After treatment for 72 hours, leptin or ET-1 concentration-dependently increased total RNA levels, cell surface areas, and protein synthesis in cardiomyocytes, all of which were significantly inhibited by ABT-627 or catalase treatment. Conclusions-These findings indicate that leptin elevates ET-1 and ROS levels, resulting in hypertrophy of cultured neonatal rat cardiac myocytes. The ET-1-ET A -ROS pathway may be involved in cardiomyocyte hypertrophy induced by leptin. ET A receptor antagonists and antioxidant therapy may provide an effective means of ameliorating cardiac dysfunction in obese humans.

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“…Expression of the respective receptors (which couple to IP 3 formation) is altered. In human heart failure, expression of α 1 -adrenergic receptors is unchanged (but their relative expression is increased due to a large downregulation of the predominating β 1 -adrenergic receptors) [196], AT 1 receptors are downregulated (presumably due to increased angiotensin II levels [197]) and ET A receptors are upregulated [198,199]. In animal models of heart failure, changes in phosphoinositide metabolism occur, including alterations in the abundance, expression and/or activity of PIP 2 , PI-4 kinase, PIP-5 kinase, PLC isoforms and inositol phosphates [200,201].…”

mentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

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168

149

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Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

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Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium

Cited by 161 publications

References 67 publications

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

Leptin Induces Hypertrophy via Endothelin-1–Reactive Oxygen Species Pathway in Cultured Neonatal Rat Cardiomyocytes

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

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