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

Sedan, Oshra; Dolnikov, Katya; Zeevi‐Levin, Naama; Leibovich, Noa; Amit, Michal; Itskovitz‐Eldor, Joseph; Binah, Ofer

doi:10.1634/stemcells.2008-0777

Cited by 44 publications

(56 citation statements)

References 29 publications

(48 reference statements)

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“…[Ca 2ϩ ] i transients and contractions were measured by means of Fura-2 fluorescence and video edge detection, respectively, routinely used in our laboratory (Dolnikov et al, 2006;Sedan et al, 2008 Measuring Intercellular Coupling by Lucifer Yellow Transfer. The scrape-loading technique was used to evaluate the degree of gap junctional intercellular communication (Kavanagh et al, 1987).…”

Section: Methodsmentioning

confidence: 99%

“…Human embryonic stem cells (hESC) from clone H9.2 were grown on mouse embryonic fibroblast feeder, and embryoid bodies prepared as described previously (Sedan et al, 2008). The contracting areas mostly composed of cardiomyocytes were carefully dissected out by a microscalpel, and transferred to gelatin-coated 30-mm-diameter glass slides suitable for fluorescent measurements (Thermo Fisher Scientific).…”

Section: Downloaded Frommentioning

confidence: 99%

“…The contracting areas mostly composed of cardiomyocytes were carefully dissected out by a microscalpel, and transferred to gelatin-coated 30-mm-diameter glass slides suitable for fluorescent measurements (Thermo Fisher Scientific). Contractions were recorded and analyzed as described previously (Dolnikov et al, 2006;Sedan et al, 2008).…”

Section: Downloaded Frommentioning

confidence: 99%

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TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Berdichevski

Meiry²,

Milman³

et al. 2009

J Pharmacol Exp Ther

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Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administrationapproved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptoticinducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicininduced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 M, 24 h) prevented doxorubicin (0.5 M, 24 h)-induced elevation of diastolic [Ca 2ϩ ] i , the slowing of [Ca 2ϩ ] i relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca 2ϩ ) ATPase, Na ϩ /Ca 2ϩ exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/ dt max ) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with doxorubicin in the treatment of malignancies in humans.

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Section: Methodsmentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

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TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Berdichevski

Meiry²,

Milman³

et al. 2009

J Pharmacol Exp Ther

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“…The electrophysiological properties were shown to be similar to mature differentiated cells in regard to ion channels and ionic currents [3,4]. The hESC-derived cardiomyocytes expressed a large sodium current density and the action potential was shortened by L-type Ca channel blockade.…”

Section: Stem Cells and Developmentmentioning

confidence: 88%

Calcium Channel Blockade in Embryonic Cardiac Progenitor Cells Disrupts Normal Cardiac Cell Differentiation

Linask¹,

Linask²

2010

Stem Cells and Development

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We suggest that characterization of processes involved in differentiation of the pluripotential cardiac precursor cells in their embryonic environment will permit identifying pathways important for induction of diverse stem cells toward the cardiac phenotype. Phenotypic characteristics of cardiac cells are their contractile and electrical properties. The objective of the present study was to define whether calcium (Ca þþ ) has a regulatory role in the pluripotential precursor cell population during commitment into cardiomyocytes. We used the chick embryo model because of ease of staging the embryos and visibility of heart development. Using the Ca þþ indicator Fluo-3=acetoxymethyl and confocal microscopy, we demonstrated the existence of higher free Ca þþ levels in the cardiogenic precursor cells than in neighboring cell populations outside of the heart fields. Subsequently, gastrulation stage 4=5 chick embryos were set up in modified New cultures in the medium containing either the L-type Ca channel blocker, diltiazem, or the N-type Ca channel inhibitor, x -conotoxin. The embryos were incubated for 22-24 h during which time the control embryos developed, beating looping hearts. At the end of incubation, exposure to the L-type channel blockade with diltiazem resulted in an inhibition of cardiomyogenesis in the most posterior, uncommitted, part of the heart fields. N-type channel blockade with x -conotoxin was less intense. Cells in the most anterior cardiogenic regions that were already committed at time of exposure continued to differentiate. Thus, regulation and maintenance of normal cytosolic Ca levels are necessary for the early steps of cardiomyocyte specification and commitment leading to differentiation.

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“…This verified the functionality of IP 3 R-channels in these cells. In H9.2 hESCs, immunostaining indicated that both IP 3 R1 and IP 3 R2 were expressed in hESC-dervied CMs (Sedan et al, 2010;Sedan et al, 2008); and the expression of IP 3 R2 was shown to gradually decline with maturation as revealed by quantitative RT-PCR (Satin et al, 2008). The expression of IP 3 R was also tested during development in vivo; its mRNA was first measured and detected as early as E5.5 in mouse embryos; it was present at high levels by E8.5 and continued to increase until E16.5 when its level started to drop (Rosemblit et al, 1999).…”

Section: Regulation Of Intracellular Calcium Level By Ligand-operatedmentioning

confidence: 99%

Maintenance Of Calcium Homeostasis in Embryonic Stem Cell-Derived Cardiomyocytes

Lo¹,

Wong²,

Tsang³

2011

Embryonic Stem Cells - Differentiation and Pluripotent Alternatives

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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

Cited by 44 publications

References 29 publications

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Calcium Channel Blockade in Embryonic Cardiac Progenitor Cells Disrupts Normal Cardiac Cell Differentiation

Maintenance Of Calcium Homeostasis in Embryonic Stem Cell-Derived Cardiomyocytes

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