Overexpression of diacylglycerol kinase zeta inhibits endothelin-1-induced decreases in Ca2+ transients and cell shortening in mouse ventricular myocytes.
Endothelin-1 (ET-1) is released in various cardiovascular disorders including congestive heart failure, and may modulate significantly the disease process by its potent action on vascular and cardiac muscle cell function and gene regulation. In adult mouse ventricular cardiomyocytes loaded with indo-1, ET-1 induced a sustained negative inotropic effect (NIE) in association with decreases in Ca(2+) transients. The ET-1-induced effects on Ca(2+) transients and cell shortening were abolished in diacylglycerol (DAG) kinase zeta-overexpressing mouse ventricular myocytes. A nonselective protein kinase C (PKC) inhibitor, GF109203X, inhibited the ET-1-induced decreases in Ca(2+) transients and cell shortening in concentration-dependent manners, whereas a selective Ca(2+)-dependent PKC inhibitor, Gö6976, did not affect the ET-1-induced effects. A phospholipase Cbeta inhibitor, U73122, and an inhibitor of phospholipase D, C(2)-ceramide, partially, but significantly, attenuated the ET-1-induced effects. Derivatives of the respective inhibitors with no specific effects, U73343 and dihydro-C(2)-ceramide, did not affect the ET-1-induced effects. Taken together, these results indicate that activation of a Ca(2+)-independent PKC isozyme by 1,2-DAG, which is generated by phospholipase Cbeta and phospholipase D activation and inactivated by phosphorylation via DAG kinase, is responsible for the ET-1-induced decreases in Ca(2+) transients and cell shortening in mouse ventricular cardiomyocytes.
Nishimaru
Kazuhide
K
Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan.
Arimoto
Takahiro
T
Takeishi
Yasuchika
Y
Kubota
Isao
I
Ishii
Kuniaki
K
Endoh
Masao
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D048430:Cell Shape / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D054799:Phospholipase C beta / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011760:Pyrrolidinones / Q000494:pharmacology
D019332:Endothelin-1; D004963:Estrenes; D007527:Isoenzymes; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D019852:Diacylglycerol Kinase; D054799:Phospholipase C beta; D010739:Phospholipase D; D002118:Calcium