Human embryonic stem cell-derived cardiomyocytes can mobilize 1,4,5-inositol trisphosphate-operated [Ca2+]i stores: the functionality of angiotensin-II/endothelin-1 signaling pathways.
Because previous findings showed that in human embryonic stem cell-derived cardiomyocytes (hESC-CM) the machinery for Ca2+-induced release of calcium is immature, we tested the hypothesis that hESC-CM contain functional 1,4,5-inositol triphosphate (IP3)-operated intracellular Ca2+ ([Ca2+]i) stores. We investigated the effects of angiotensin II (AT-II) and endothelin 1 (ET-1), which activate the 1,4,5-IP3 pathway, on [Ca2+]i transients and contractions in hESC-CM. Our major findings were that in hESC-CM, both AT-II (10(-9)-10(-7) M) and ET-1 (10(-9)-10(-7) M) exert inotropic and lusitropic effects. The involvement of 1,4,5-IP3-dependent intracellular Ca2+ release in AT-I-induced effects was supported by these findings: the effects of AT-II were blocked by 2-aminoethoxyphenyl borate (2-APB, a 1,4,5-IP3 receptor blocker) and U73122 (a phosopholipase C blocker); and hESC-CM express AT-II type 1 and IP3 type I and II receptors as determined by fluorescence immunostaining. In conclusion, hESC-CM exhibit functional AT-II and ET-1 signaling pathways, as well as 1,4,5-IP3-operated releasable Ca2+ stores.
Sedan
Oshra
O
Ruth and Bruce Rappaport Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, TechnionIsrael Institute of Technology, Haifa, Israel.
Dolnikov
Katya
K
Zeevi-Levin
Naama
N
Fleishmann
Noa
N
Spiegel
Idit
I
Berdichevski
Sasha
S
Amit
Michal
M
Itskovitz-Eldor
Joseph
J
Binah
Ofer
O
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction
D019332:Endothelin-1; D000804:Angiotensin II; D002118:Calcium