Abstract
Aim:
Intracellular Ca2+ plays pivotal roles in diverse cellular functions, including gene transcription that underlies cardiac remodeling during stress responses. However, the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the mediation of cardiac intracellular Ca2+ and hypertrophic growth remains elusive. Prior work with neonatal rat ventricular myocytes suggests that activation of IP3Rs may be linked to α1 adrenergic receptor (α1 AR) increased stereotyped Ca2+ spark occurrence and global Ca2+ oscillations. Thus, we hypothesized that Ca2+ release through IP3Rs was necessary for α1 AR-stimulated cardiac hypertrophy.
Methods:
We used myoinositol 1,4,5-trisphosphate hexakis (butyryloxymethyl) ester (IP3BM), a membrane-permeant ester of IP3, to activate IP3Rs directly, and Fluo 4/AM to measure intracellular Ca2+ signaling.
Results:
IP3BM (10 μmol-L−1) mimicked the effects of phenylephrine, a selective agonist of α1AR, in increments in local Ca2+ spark release (especially in the perinuclear area) and global Ca2+ transient frequencies. More importantly, IP3R inhibitors, 2-aminoethoxydiphenyl borate and Xestospongin C, abolished the IP3BM-induced Ca2+ responses, and significantly suppressed α1AR-induced cardiomyocyte hypertrophy assayed by cell size, [3H] leucine incorporation and atrial natriuretic factor gene expression, during sustained (48 h) phenylephrine stimulation.
Conclusion:
These results, therefore, provide cellular mechanisms that link IP3R signaling to α1 AR-stimulated gene expression and cardiomyocyte hypertrophy.
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Project supported by the National Natural Science Foundation of China (No 30470692).
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Luo, Dl., Gao, J., Lan, Xm. et al. Role of inositol 1,4,5-trisphosphate receptors in α1-adrenergic receptor-induced cardiomyocyte hypertrophy. Acta Pharmacol Sin 27, 895–900 (2006). https://doi.org/10.1111/j.1745-7254.2006.00382.x
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DOI: https://doi.org/10.1111/j.1745-7254.2006.00382.x
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