TY - JOUR
T1 - The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes
AU - Barac, Yaron D.
AU - Zeevi-Levin, Naama
AU - Yaniv, Gal
AU - Reiter, Irina
AU - Milman, Felix
AU - Shilkrut, Mark
AU - Coleman, Raymond
AU - Abassi, Zaid
AU - Binah, Ofer
N1 - Funding Information:
This work was supported by Servier through the Center of Molecular Therapeutics at Columbia University–New York, the Israel Academy of Sciences, Minerva Foundation through the Bernard Katz Center for Cell Biophysics and the Rappaport Institute. We wish to acknowledge the help of Ofer Shenkar and Edith Suss from the Department of Interdisciplinary Equipment, and Dr. Noam Ziv from the Department of Anatomy and Cell Biology.
PY - 2005/10/1
Y1 - 2005/10/1
N2 - Objective: Cardiac hypertrophy is a compensatory response to increased mechanical load. Since Fas receptor activation is an important component in hypertrophy induced by pressure- and volume-overload, deciphering the underlying signaling pathways is of prime importance. Based on our previous work showing that in mice and rats ventricular myocytes the electrophysiological disturbances and diastolic [Ca2+]i-rise caused by 3 h of Fas activation are dependent on the Fas → phospholipase C (PLC) → 1,4,5-inositol trisphosphate (1,4,5-IP3) → sarcoplasmic reticulum (SR) [Ca2+]i release pathway, we tested the hypothesis that this pathway is also critical for Fas-mediated hypertrophy. Methods: The effects of 24 h Fas activation in cultured neonatal rat ventricular myocytes (NRVM) were analyzed by means of RT-PCR, Western blot, immunofluorescence and fura-2 fluorescence. Results: Fas activation increased nuclei surface area, atrial natriuretic peptide and connexin43 (Cx43) mRNA, the protein levels of total Cx43 and non-phosphorylated Cx43, and sarcomeric actin, all indicating hypertrophy. Concomitantly, Fas activation decreased mRNA of SERCA2a, the ryanodine receptor (RyR) and nuclear IP3R3. Further, Fas activation caused NFAT nuclear translocation. The hypertrophy was abolished by U73122, xestospongin C (blockers of the 1,4,5-IP3 pathway), genistein and by the PI3K blocker LY294002. Conclusions: Fas-mediated hypertrophy is dependent on the 1,4,5-IP3 pathway, which is functionally inter-connected to the PI3K/AKT/GSK3β pathway. Both pathways act in concert to cause NFAT nuclear translocation and subsequent hypertrophy.
AB - Objective: Cardiac hypertrophy is a compensatory response to increased mechanical load. Since Fas receptor activation is an important component in hypertrophy induced by pressure- and volume-overload, deciphering the underlying signaling pathways is of prime importance. Based on our previous work showing that in mice and rats ventricular myocytes the electrophysiological disturbances and diastolic [Ca2+]i-rise caused by 3 h of Fas activation are dependent on the Fas → phospholipase C (PLC) → 1,4,5-inositol trisphosphate (1,4,5-IP3) → sarcoplasmic reticulum (SR) [Ca2+]i release pathway, we tested the hypothesis that this pathway is also critical for Fas-mediated hypertrophy. Methods: The effects of 24 h Fas activation in cultured neonatal rat ventricular myocytes (NRVM) were analyzed by means of RT-PCR, Western blot, immunofluorescence and fura-2 fluorescence. Results: Fas activation increased nuclei surface area, atrial natriuretic peptide and connexin43 (Cx43) mRNA, the protein levels of total Cx43 and non-phosphorylated Cx43, and sarcomeric actin, all indicating hypertrophy. Concomitantly, Fas activation decreased mRNA of SERCA2a, the ryanodine receptor (RyR) and nuclear IP3R3. Further, Fas activation caused NFAT nuclear translocation. The hypertrophy was abolished by U73122, xestospongin C (blockers of the 1,4,5-IP3 pathway), genistein and by the PI3K blocker LY294002. Conclusions: Fas-mediated hypertrophy is dependent on the 1,4,5-IP3 pathway, which is functionally inter-connected to the PI3K/AKT/GSK3β pathway. Both pathways act in concert to cause NFAT nuclear translocation and subsequent hypertrophy.
KW - Calcium (cellular)
KW - Cell culture
KW - Hypertrophy
KW - Myocytes
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=24344437772&partnerID=8YFLogxK
U2 - 10.1016/j.cardiores.2005.05.015
DO - 10.1016/j.cardiores.2005.05.015
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C2 - 16005448
AN - SCOPUS:24344437772
SN - 0008-6363
VL - 68
SP - 75
EP - 86
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -