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1,4,5‐Inositol Trisphosphate‐Operated Intracellular Ca2+ Stores and Angiotensin‐II/Endothelin‐1 Signaling Pathway Are Functional in Human Embryonic Stem Cell‐Derived Cardiomyocytes

On the basis of previous findings suggesting that in human embryonic stem cell‐derived cardiomyocytes (hESC‐CM) the sarcoplasmic reticulum Ca2+‐induced release of calcium machinery is either absent or immature, in the present study we tested the hypothesis that hESC‐CM contain fully functional 1,4,5‐inositol trisphosphate (1,4,5‐IP3)‐operated intracellular Ca2+ ([Ca2+]i) stores that can be mobilized upon appropriate physiological stimuli. To test this hypothesis 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 beating clusters of hESC‐CM. Our major findings were that in paced hESC‐CM both AT‐II and ET‐1 (10−9 to 10−7 M) increased the contraction amplitude and the maximal rates of contraction and relaxation. In addition, AT‐II (10−9 to 10−7 M) increased the [Ca2+]i transient amplitude. The involvement of 1,4,5‐IP3‐dependent intracellular Ca2+ release in the inotropic effect of AT‐II was supported by the findings that (a) hESC‐CM express AT‐II, ET‐1, and 1,4,5‐IP3 receptors determined by immunofluorescence staining, and (b) the effects of AT‐II were blocked by 2 μM 2‐aminoethoxyphenyl borate (a 1,4,5‐IP3 receptor blocker) and U73122 (a phospholipase C blocker). In conclusion, these findings demonstrate for the first time that hESC‐CM exhibit functional AT‐II and ET‐1 signaling pathways, as well as 1,4,5‐IP3‐operated releasable Ca2+ stores.