Original Article

Acta Pharmacologica Sinica (2006) 27, 895–900; doi:10.1111/j.1745-7254.2006.00382.x

Role of inositol 1,4,5-trisphosphate receptors in alpha1-adrenergic receptor-induced cardiomyocyte hypertrophy

Project supported by the National Natural Science Foundation of China (No 30470692).

Da-li Luo2,3, Jian Gao2, Xiao-mei Lan3, Gang Wang4, Sheng Wei4, Rui-ping Xiao4 and Qi-de Han3

  1. 2Department of Pharmacology, School of Chemical Biology & Pharmaceutical Sciences, Capital University of Medical Sciences, Beijing 100069, China
  2. 3Institute of Cardiovascular Science at Health Science Center, Peking University, Beijing 100083, China
  3. 4Institute of Molecular Medicine and College of Life Science, Peking University, Beijing 100871, China

Correspondence: Dr Da-li Luo, Fax: 86-10-8391-1520. E-mail: luodl@bjmu.edu.cn

Received 18 April 2006; Accepted 17 May 2006.

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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 alpha1 adrenergic receptor (alpha1 AR) increased stereotyped Ca2+ spark occurrence and global Ca2+ oscillations. Thus, we hypothesized that Ca2+ release through IP3Rs was necessary for alpha1 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 mumol-L-1) mimicked the effects of phenylephrine, a selective agonist of alpha1AR, 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 alpha1AR-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 alpha1 AR-stimulated gene expression and cardiomyocyte hypertrophy.

Keywords:

inositol 1,4,5-trisphosphate receptors, Ca2+ sparks, alpha1 adrenergic stimulation, cardiac hypertrophy

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