Endothelin-1 as a protective factor against beta-adrenergic agonist-induced apoptosis in cardiac myocytes.
OBJECTIVE
The purpose of this study was to investigate the regulation of beta-adrenergic agonist-induced apoptosis by endothelin-1 (ET-1) in cardiac myocytes.


BACKGROUND
Numerous hormonal factors including norepinephrine and ET-1 are activated in patients with heart failure. These factors may be involved in the positive and negative regulation of myocardial cell apoptosis observed in failing hearts. Recently, it has been shown that norepinephrine can induce myocardial cell apoptosis via a beta-adrenergic receptor-dependent pathway.


METHODS
Primary cardiac myocytes were prepared from neonatal rats. These cells were stimulated with the beta-adrenergic agonist isoproterenol (ISO) in the presence or absence of ET-1.


RESULTS
The administration of 10(-7) mol/liter of ET-1 completely blocked Iso-induced apoptosis. An endothelin type A receptor antagonist, FR139317, negated the inhibitory effect of ET-1 on apoptosis, while the endothelin type B receptor antagonist BQ788 did not show such a negation. Endothelin-1 also inhibited apoptosis induced by a membrane-permeable cAMP analogue (8-Br-cAMP), which bypassed Gi. The effect of ET-1 was neutralized by an MEK-1-specific inhibitor (PD098059), a phosphatidylinositol 3'-kinase inhibitor (wortmannin) and its downstream pp70 S6-kinase inhibitor, rapamycin.


CONCLUSIONS
These findings suggest that ET-1 represents a protective factor against myocardial cell apoptosis in heart failure and that this effect is mediated mainly through endothelin type A receptor-dependent pathways involving multiple downstream signalings in cardiac myocytes.
Araki
M
M
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan.
Hasegawa
K
K
Iwai-Kanai
E
E
Fujita
M
M
Sawamura
T
T
Kakita
T
T
Wada
H
H
Morimoto
T
T
Sasayama
S
S
D000318:Adrenergic beta-Agonists / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000633:toxicity; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000633:toxicity*; D009206:Myocardium / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D020123:Sirolimus / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000900:Anti-Bacterial Agents; D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D009842:Oligopeptides; D010880:Piperidines; D044022:Receptor, Endothelin A; C079574:FR 139317; C016276:8-bromocyclic GMP; C086539:BQ 788; D017869:Cyclic GMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006152:Cyclic GMP; D007545:Isoproterenol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus