Increased production of endothelin‐1 in the hypertrophied rat heart due to pressure overload

Yorikane, Ryosuke; Sakai, Satoshi; Miyauchi, Takashi; Sakurai, Takeshi; Sugishita, Yasuro; Goto, Katsutoshi

doi:10.1016/0014-5793(93)80476-b

Cited by 106 publications

(46 citation statements)

References 19 publications

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“…In cell cultures of cardiomyocytes, ET-1 induces hypertrophy as assessed by cell size, increased myofibrillogenesis, and transcriptional changes associated with cardiac hypertrophy such as expression of atrial natriuretic factor (3,4). Of note, in these studies the concentrations of ET-1 required to produce hypertrophy were 10 Ϫ7 to 10 Ϫ9 M, far greater than those encountered in plasma (10 Ϫ12 to 10 Ϫ13 M) (5). Although cardiac synthesis of ET-1 is negligible under normal circumstances, conditions that stimulate hypertrophy markedly increase expression of ET-1 mRNA in cardiac cells (6).…”

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confidence: 78%

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Shohet

Kisanuki

Zhao

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Endothelin 1 (ET-1), a potent vasoconstrictor peptide expressed by endothelium, is also produced in the heart in response to a variety of stresses. It induces hypertrophy in cultured cardiac myocytes but only at concentrations far greater than those found in plasma. We tested whether ET-1 generated by cardiac myocytes in vivo is a local signal for cardiac hypertrophy. To avoid the perinatal lethality seen in systemic ET-1-null mice, we used the Cre͞loxP system to generate mice with cardiac myocyte-specific disruption of the ET-1 gene. We used the ␣-myosin heavy chain promoter to drive expression of Cre and were able to obtain 75% reduction in ET-1 mRNA in cardiac myocytes isolated from these mice at baseline and after stimulation, in vivo, for 24 h with tri-iodothyronine (T3). Necropsy measurements of cardiac mass indexed for body weight showed a 57% reduction in cardiac hypertrophy in response to 16 days of exogenous T3 in mice homozygous for the disrupted ET-1 allele compared to siblings with an intact ET-1 gene. Moreover, in vivo MRI showed only a 3% increase in left ventricular mass indexed for body weight in mice with the disrupted allele after 3 weeks of T3 treatment versus a 27% increase in mice with an intact ET-1 gene. A reduced hypertrophic response was confirmed by planimetry of cardiac myocytes. We conclude that ET-1, produced locally by cardiac myocytes, and acting in a paracrine͞autocrine manner, is an important signal for myocardial hypertrophy that facilitates the response to thyroid hormone. C ardiac hypertrophy is characterized by an increase in myocardiocyte size and is accompanied by qualitative and quantitative changes in gene expression, protein synthesis, and physiological performance (1). Cardiac hypertrophy helps to maintain cardiac output in the presence of increased demand or afterload, yet it is one of the most important predisposing risk factors for sudden death and the development of heart failure in human populations. A greater understanding of hypertrophy, and the capacity to regulate it in human disease, could have profound clinical implications.Many ligand͞receptor systems, with their specific and interwoven downstream signaling pathways, have been implicated in cardiomyocyte hypertrophy in both cell culture and intact animals (reviewed in ref.2). These include the peptide endothelin 1 (ET-1) and its receptors ET A and ET B on the cell surface of cardiomyocytes. Several lines of evidence suggest that ET-1 functions in a paracrine͞autocrine manner in cardiac hypertrophy. In cell cultures of cardiomyocytes, ET-1 induces hypertrophy as assessed by cell size, increased myofibrillogenesis, and transcriptional changes associated with cardiac hypertrophy such as expression of atrial natriuretic factor (3, 4). Of note, in these studies the concentrations of ET-1 required to produce hypertrophy were 10 Ϫ7 to 10 Ϫ9 M, far greater than those encountered in plasma (10 Ϫ12 to 10 Ϫ13 M) (5). Although cardiac synthesis of ET-1 is negligible under normal circumstances, conditions that stimulate...

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confidence: 78%

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Shohet

Kisanuki

Zhao

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.). A rat model of pressure overload was prepared according to a previously described method (27). The abdominal aorta was constricted between the right and left renal arteries, using a 23-gauge needle to establish the diameter of the ligature.…”

Section: Animals and Preparationmentioning

confidence: 99%

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Shimizu

Ishibashi

Kumagai

et al. 2013

International Journal of Molecular Medicine

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Abstract. Sustained cardiac pressure overload induces mitochondrial dysfunction and apoptosis of cardiomyocytes leading to pathological cardiac hypertrophy and dysfunction. Mitochondrial nitric oxide synthase (NOS) appears to cause uncoupling, which produces reactive oxygen species (ROS) instead of nitric oxide (NO), by a decrease in the cofactor tetrahydrobiopterin (BH4). This study focused on examining the changes in mitochondrial BH4 levels during cardiac pressure overload. Chronic cardiac pressure overload was generated by abdominal aortic banding in rats. Levels of BH4 and its oxidized form were measured in the mitochondria isolated from the left ventricle (LV) and the post-mitochondrial supernatants. Chronic aortic banding increased blood pressure, and induced cardiac hypertrophy and fibrosis. Notably, the BH4 levels were decreased while its oxidized forms were increased in LV mitochondria, but not in the post-mitochondrial supernatants containing the cytosol and microsome. Anti-neuronal NOS antibody-sensitive protein was detected in the cardiac mitochondria. Moreover, continuous administration of BH4 to rats with pressure overload increased mitochondrial BH4 levels and reduced cardiac fibrosis and matrix metallopeptidase activity, but not cardiac hypertrophy. These findings show the possibility that NOS uncoupling by decreased cardiac mitochondrial BH4 levels is implicated, at least in part, in the development of cardiac fibrosis, leading to cardiac dysfunction induced by pressure overload.

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“…[11][12][13][14] The expression of preproET-1 and BNP mRNA and the transition of ␣-MHC to ␤-MHC mRNA, the alterations of which are regarded as molecular markers of cardiac hypertrophy, were investigated according to our previous report. 14 The expression of 18 S ribosomal RNA was determined as an internal control.…”

Section: Hemodynamic Measurement Tissue Sampling and Mrna Expressionmentioning

confidence: 99%

“…10 The ET-1 gene has AP-1 binding sites in the promoter region, and these factors are known to upregulate AP-1, suggesting that the ET-1 gene is partly induced through AP-1 binding. 6 We have reported that the production of ET-1 is markedly increased both in the hypertrophied heart and the failing heart [11][12][13][14] and that chronic treatment with ET type A receptor antagonists significantly inhibited the development of cardiac hypertrophy and heart failure. 11,13,14 These data suggest that ET-1 plays an important role in the development of cardiac hypertrophy and heart failure, both in vitro and in vivo.…”

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confidence: 99%

Endothelin-1–Induced Cardiac Hypertrophy Is Inhibited by Activation of Peroxisome Proliferator–Activated Receptor-α Partly Via Blockade of c-Jun NH ₂ -Terminal Kinase Pathway

Irukayama-Tomobe

Miyauchi²,

Sakai³

et al. 2004

Circulation

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108

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Background-Peroxisome proliferator-activated receptor-␣ (PPAR-␣) is a lipid-activated nuclear receptor that negatively regulates the vascular inflammatory gene response by interacting with transcription factors, nuclear factor-B, and AP-1. However, the roles of PPAR-␣ activators in endothelin (ET)-1-induced cardiac hypertrophy are not yet known. Methods and Results-First, in cultured neonatal rat cardiomyocytes, a PPAR-␣ activator, fenofibrate (10 mol/L), and PPAR-␣ overexpression markedly inhibited the ET-1-induced increase in protein synthesis. Second, fenofibrate markedly inhibited ET-1-induced increase in c-Jun gene expression and phosphorylation of c-Jun and JNK. These results suggest that this PPAR-␣ activator interferes with the formation and activation of AP-1 protein induced by ET-1 in cardiomyocytes. Third, fenofibrate significantly inhibited the increase of ET-1 mRNA level by ET-1, which was also confirmed by luciferase assay. Electrophoretic mobility shift assay revealed that fenofibrate significantly decreased the ET-1-stimulated or phorbol 12-myristate 13-acetate-stimulated AP-1 DNA binding activity, and the nuclear extract probe complex was supershifted by anti-c-Jun antibody. Fourth, 24 hours after aortic banding (AB) operation, fenofibrate treatment significantly inhibited left ventricular hypertrophy and hypertrophy-related gene expression pattern (ET-1, brain natriuretic peptide, and ␤-myosin heavy chain mRNA) in AB rats. Conclusions-These results suggest that PPAR-␣ activation interferes with the signaling pathway of ET-1-induced cardiac hypertrophy through negative regulation of AP-1 binding activity, partly via inhibition of the JNK pathway in cultured cardiomyocytes. We also revealed that fenofibrate treatment inhibited left ventricle hypertrophy and phenotypic changes in cardiac gene expression in AB rats in vivo.

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Increased production of endothelin‐1 in the hypertrophied rat heart due to pressure overload

Cited by 106 publications

References 19 publications

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Endothelin-1–Induced Cardiac Hypertrophy Is Inhibited by Activation of Peroxisome Proliferator–Activated Receptor-α Partly Via Blockade of c-Jun NH ₂ -Terminal Kinase Pathway

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Increased production of endothelin‐1 in the hypertrophied rat heart due to pressure overload

Cited by 106 publications

References 19 publications

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Endothelin-1–Induced Cardiac Hypertrophy Is Inhibited by Activation of Peroxisome Proliferator–Activated Receptor-α Partly Via Blockade of c-Jun NH 2 -Terminal Kinase Pathway

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Endothelin-1–Induced Cardiac Hypertrophy Is Inhibited by Activation of Peroxisome Proliferator–Activated Receptor-α Partly Via Blockade of c-Jun NH ₂ -Terminal Kinase Pathway