Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

Yang, Li; Gros, Robert; Kabir, M. Golam; Sadi, Al-Muktafi; Gotlieb, Avrum I.; Husain, Mansoor; Stewart, Duncan J.

doi:10.1161/01.cir.0000105701.98663.d4

Cited by 155 publications

(126 citation statements)

References 47 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…Similar characteristics of cardiomyopathy such as significantly lower LV pressure and dP/dt max were also found in mice overexpressing ET-1 orthotopically in cardiomyocytes (4). This led to the hypothesis that ET-1 might be an important mediator of doxorubicin cardiotoxicity.…”

Section: Discussionmentioning

confidence: 53%

“…However, the results of these studies were neutral in terms of mortality and symptoms (24), leading to an intense discussion on whether the use of receptor subtype-specific endothelin receptor blockers may be of advantage. Interestingly, the above cited study by Yang and coworkers showed that the combined ET A /ET B antagonist LU420627, but not the selective ET A antagonist LU135252, prolonged the survival of ET-1-overexpressing cardiomyopathic mice (4).…”

Section: Discussionmentioning

confidence: 98%

“…In addition, mechanistic studies in mice by Yang and colleagues revealed that cardiacspecific overexpression of ET-1 leads to cardiomyopathy and left ventricle (LV) dysfunction combined with inflammatory characteristics such as increased tumor necrosis factor-a (TNFa) content and interstitial inflammatory infiltrates (4). Moreover, ET-1 has been implicated in the progression of CHF because the expression of ET-1 and its receptors are elevated in the myocardium of rats with CHF and in patients with idiopathic dilated cardiomyopathy (5,6).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

et al. 2007

View full text Add to dashboard Cite

Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiacspecific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-A content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.

show abstract

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Thus, it has been proposed that ETA, the prevalent receptor subtype in the cardiac tissue, mediates the main cellular functions of endothelin, whereas ETB is involved in the clearance of ET-1. However, since ET-3 also evokes a hypertrophic response [7] and the pathogenic effects of conditional, myocyte-specific ET-1 overexpression are delayed by a mixed ETA/ETB antagonist but not an ETA-selective antagonist [8], ETB also plays an important functional role in adult cardiac ventricular myocytes.…”

Section: Introductionmentioning

confidence: 99%

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

Merlen¹,

Farhat²,

Luo³

et al. 2013

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Endothelin receptors are present on the nuclear membranes in adult cardiac ventricular myocytes. The objectives of the present study were to determine 1) which endothelin receptor subtype is in cardiac nuclear membranes, 2) if the receptor and ligand traffic from the cell surface to the nucleus, and 3) the effect of increased intracellular ET-1 on nuclear Ca 2+ signalling. Confocal microscopy using fluorescently-labeled endothelin analogs confirmed the presence of ETB at the nuclear membrane of rat cardiomyocytes in skinned-cells and isolated nuclei. Furthermore, in both cardiac myocytes and aortic endothelial cells, endocytosed ET:ETB complexes translocated to lysosomes and not the nuclear envelope. Although ETA and ETB can form heterodimers, the presence or absence of ETA did not alter ETB trafficking. Treatment of isolated nuclei with * Abbreviations: The abbreviations used are: 2-APB, 2-aminoethoxydiphenyl borate; A, Angiotensin II; αAR, α-adrenergic receptor;[Ca 2+ ] n , nucleoplasmic free calcium concentration; CaMKII, Ca 2+ /calmodulin-dependent protein kinase II; DMNB, 4,5-dimethoxynitrobenzyl group; DNA, deoxyribonucleic acid; DCC, 1,3-dicyclohexylcarbodiimide; DCM, dichloromethane; DTT, dithiothreitol; ECE1-a, endothelin converting enzyme 1a; cET-1, caged ET-1; caged ET-1, [Trp-ODMNB 21 ]ET-1; ET-1, endothelin 1; ET-2, endothelin 2; ET-3, endothelin 3; ETA, endothelin type A receptor; ETB, endothelin type B receptor; ETR, endothelin receptor; GPCR, G protein-coupled receptor; HDAC5; histone deacetylase 5; IP3, inositol 1,4,5-trisphosphate; IP3R, inositol 1,4,5-trisphosphate receptor; ISO, isoproterenol; MEF2, myocyte enhancing factor-2; PBS, phosphate buffered saline; PMSF, phenylmethanesulphonylfluoride; PNGase F, peptide N-glycosidase F; qPCR, quantitative real-time polymerase chain reaction; RNA, ribonucleic acid; RyR, ryanodine receptor; TCA, trichloroacetic acid; TFA, trifluoroacetic acid; TX-100, Triton X-100. Address correspondence to: Bruce G. Allen, Montreal Heart Institute, 5000 Belanger St,. Montréal, Québec, Canada, H1T 1C8., Telephone: (514) ] n whereas extracellular application of ETA and ETB receptor antagonists did not. These data suggest that 1) the endothelin receptor in the cardiac nuclear membranes is ETB, 2) ETB traffic directly to the nuclear membrane after biosynthesis, 3) exogenous endothelins are not ligands for ETB on nuclear membranes, and 4) ETB associated with the nuclear membranes regulate nuclear Ca 2+ signalling.

show abstract

“…In congestive heart failure, NGF levels in the heart decrease (21) as plasma norepinephrine levels rise; concomitantly, ET-1 plasma levels rise as well (22), although it is not clear how these changes are interrelated. Additionally, a recent report suggests that ET-1 overexpression in the adult mouse heart leads to a dilated cardiomyopathy and death (23). Given the developmental role of ET-1 in regulating NGF production by cardiac myocytes, evaluation of similar actions in the adult heart, and secondary effects on sympathetic function, may be warranted.…”

Section: Figurementioning

confidence: 99%

Sculpting organ innervation

Hempstead¹

2004

J. Clin. Invest.

View full text Add to dashboard Cite

Neurotrophic growth factors, including nerve growth factor (NGF) and glialderived neurotrophic factor (GDNF), have well-established roles in promoting the innervation of target tissues, yet little is known about how the temporal and organ-specific expression of these factors is regulated. A new study (see the related article beginning on page 876) reveals that NGF is a direct target of the well-characterized peptide factor endothelin-1 (ET-1), and that ET-1-induced NGF expression is required for sympathetic innervation of the developing heart. These results, and recent studies implicating GDNF and ET-3 in the patterning of the enteric nervous system, suggest that specific pairing of endothelins and neurotrophic factors may be used in distinct target organs to coordinate neuronal migration, differentiation, and survival.

show abstract

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

Cited by 155 publications

References 47 publications

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

Sculpting organ innervation

Contact Info

Product

Resources

About