Endogenous Endothelin-1 Participates in the Maintenance of Cardiac Function in Rats With Congestive Heart Failure

Sakai, Satoshi; Miyauchi, Takashi; Sakurai, Takeshi; Kasuya, Yoshitoshi; Ihara, Masaki; Yamaguchi, Iwao; Goto, Katsutoshi; Sugishita, Yasuro

doi:10.1161/01.cir.93.6.1214

Cited by 263 publications

(143 citation statements)

References 48 publications

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“…We used the left coronary artery-ligated rat model of CHF, which is well established (24,(26)(27)(28). To produce rats with CHF, left ventricular free wall myocardial infarction was induced in 7-wk-old male rats (CHF group) according to the method described in our previous papers (26)(27)(28).…”

Section: Animals and Protocolmentioning

confidence: 99%

Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training

Iemitsu

Miyauchi

Maeda

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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150

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Peroxisome proliferator-activated receptor (PPAR)-␣, a transcriptional activator, regulates genes of fatty acid (FA) metabolic enzymes. To study the contribution of PPAR-␣ to exercise training-induced improvement of FA metabolic capacity in the aged heart, we investigated whether PPAR-␣ signaling and expression of its target genes in the aged heart are affected by exercise training. We used hearts of sedentary young rat (4 mo old), sedentary aged rat (23 mo old), and swim-trained aged rat (23 mo old, training for 8 wk). The mRNA and protein expression of PPAR-␣ in the heart was significantly lower in the sedentary aged rats compared with the sedentary young rats and was significantly higher in the swim-trained aged rats compared with the sedentary aged rats. The activity of PPAR-␣ DNA binding to the transcriptional regulating region on the FA metabolic enzyme genes, the mRNA expression of 3-hydroxyacyl CoA dehydrogenase (HAD) and carnitine palmitoyl transferase-I, which are PPAR-␣ target genes, and the enzyme activity of HAD in the heart altered in association with changes of the myocardial PPAR-␣ mRNA and protein levels. These findings suggest that exercise training improves aging-induced downregulation in myocardial PPAR-␣-mediated molecular system, thereby contributing to the improvement of the FA metabolic enzyme activity in the trained-aged hearts.peroxisome proliferator-activated receptor-␣; swimming training; aged rat; fatty acid THE HEART is known for its ability to produce energy from fatty acids (FA) because of its important ␤-oxidation equipment, but it can also derive energy from several other substrates, including glucose and lactate (10, 23). On a physiological condition, FA is considered to account for 60-70% of oxygen consumption for energy production in the heart (23). However, FA metabolic capacity in the heart is reduced by aging (19, 32).It has been reported that exercise training improved an aging-induced decrease of FA metabolic capacity in the heart (7, 18, 25, 32). However, the mechanisms for improving FA metabolic capacity in the heart by exercise training are unclear.Peroxisome proliferator-activated receptor (PPAR)-␣ is a member of the nuclear receptor transcription factor superfamily and is mainly expressed in the heart, liver, and kidney (2,13,29). The recent studies indicated that PPAR-␣ plays a critical role in the expression of genes involved in FA metabolism (13). PPAR-␣ heterodimerizes with the retinoid X receptor (RXR-␣) to bind to peroxisome proliferator-response elements (PPRE) in the upstream regions of a number of genes involved in metabolic homeostasis (13,29). PPAR-␣ regulates target genes encoding FA metabolic (␤-oxidation) enzymes and FA transporters such as FA binding protein, carnitine palmitoyl transferase-I (CPT-I), acyl-CoA synthase, 3-hydroxyacyl CoA dehydrogenase (HAD), apolipoproteins, and so on, suggesting that PPAR-␣ plays an important role in FA metabolic homeostasis (2,5,17,29). However, it is unknown whether the aging and subsequent exercise training affect...

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Section: Animals and Protocolmentioning

confidence: 99%

Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training

Iemitsu

Miyauchi

Maeda

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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150

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“…It is produced within both failing and nonfailing hearts from several types of cells, including endothelial cells (137), endocardium, and myocytes (138). It has been considered that limited expression of endothelin-1 within the myocardium is an adaptive response to stress, providing increased inotropic support for the cardiac myocyte (139,140) as well as increasing the rate of myocyte protein synthesis (141). Overexpression of endothelin-1, however, eventually becomes maladaptive by producing focal vasospasm, myocytosis, and increased myocardial fibrosis (142).…”

Section: Cytokines and Other Factors In Myocardial Death Signalingmentioning

confidence: 99%

Molecular and cellular mechanisms of cardiotoxicity.

Kang

2001

Environ Health Perspect

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Cardiotoxicity resulting from detrimental environmental insults has been recognized for a long time. However, extensive studies of the mechanisms involved had not been undertaken until recent years. Advances in molecular biology provide powerful tools and make such studies possible. We are gathering information about cellular events, signaling pathways, and molecular mechanisms of myocardial toxicologic responses to environmental toxicants and pollutants. Severe acute toxic insults cause cardiac cell death instantly. In the early response to mild environmental stimuli, biochemical changes such as alterations in calcium homeostasis occur. These may lead to cardiac arrhythmia, which most often is reversible. Prolonged stimuli activate transcription factors such as activator protein-1 through elevation of intracellular calcium and the subsequent activation of calcineurin. Upregulation by activated transcription factors of hypertrophic genes results in heart hypertrophy, which is a short-term adaptive response to detrimental factors. However, further development of hypertrophy will lead to severe and irreversible cardiomyopathy, and eventually heart failure. From cardiac hypertrophy to heart failure, myocardial cells undergo extensive biochemical and molecular changes. Cardiac hypertrophy causes tissue hypoperfusion, which activates compensatory mechanisms such as production of angiotensin II and norepinephrine. Both further stimulate cardiac hypertrophy and, importantly, activate counterregulatory mechanisms including overexpression of atrial natriuretic peptide and b-type natriuretic peptide, and production of cytokines such as tumor necrosis factor-alpha. This counterregulation leads to myocardial remodeling as well as cell death through apoptosis and necrosis. Cell death through activation of mitochondrial factors and other pathways constitutes an important cellular mechanism of heart failure. Our current knowledge of cardiotoxicity is limited. Further extensive studies are warranted for a comprehensive understanding of this field.

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“…These findings are clear evidence that endothelin-1 does contribute to the maintenance of vascular tone in such patients. Supporting evidence comes from observations in rats with heart failure one month after myocardial infarction induced by left coronary artery ligation, where it was shown that systemic infusion of BQ-123 decreased both myocardial contractility and heart rate (276). Furthermore, in rats with infarction, the surviving myocardium expressed a markedly increased amount of endothelin-1 as well as its receptors (276), suggesting that endogenous endothelin-1 might help to support cardiac function in the setting of myocardial failure through the upregulated endothelin system.…”

Section: V-6 Cardiac Hypertrophymentioning

confidence: 96%

“…Supporting evidence comes from observations in rats with heart failure one month after myocardial infarction induced by left coronary artery ligation, where it was shown that systemic infusion of BQ-123 decreased both myocardial contractility and heart rate (276). Furthermore, in rats with infarction, the surviving myocardium expressed a markedly increased amount of endothelin-1 as well as its receptors (276), suggesting that endogenous endothelin-1 might help to support cardiac function in the setting of myocardial failure through the upregulated endothelin system. In porcine heart subjected to ischemia by means of coronary artery occlusion, increased expression and production of endothelin-1 was detected in cardiac myocytes but not in coronary vascular endothelial or smooth muscle cells (277).…”

Section: V-6 Cardiac Hypertrophymentioning

confidence: 96%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

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158

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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Endogenous Endothelin-1 Participates in the Maintenance of Cardiac Function in Rats With Congestive Heart Failure

Cited by 263 publications

References 48 publications

Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training

Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training

Molecular and cellular mechanisms of cardiotoxicity.

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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