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

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 a1 adrenergic receptor (alpha1AR) increased stereotyped Ca2+ spark occurrence and global Ca2+ oscillations. Thus, we hypothesized that Ca2+ release through IP3Rs was necessary for alpha1AR-stimulated cardiac hypertrophy.
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.
IP3BM (10 micromol x 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.
These results, therefore, provide cellular mechanisms that link IP3R signaling to alpha1AR-stimulated gene expression and cardiomyocyte hypertrophy.
AuthorsDa-li Luo, Jian Gao, Xiao-mei Lan, Gang Wang, Sheng Wei, Rui-ping Xiao, Qi-de Han
JournalActa pharmacologica Sinica (Acta Pharmacol Sin) Vol. 27 Issue 7 Pg. 895-900 (Jul 2006) ISSN: 1671-4083 [Print] China
PMID16787574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2-aminoethoxydiphenyl borate
  • Adrenergic alpha-1 Receptor Agonists
  • Boron Compounds
  • Inositol 1,4,5-Trisphosphate Receptors
  • Macrocyclic Compounds
  • Oxazoles
  • RNA, Messenger
  • xestospongin C
  • Phenylephrine
  • Atrial Natriuretic Factor
  • Leucine
  • Calcium
  • Adrenergic alpha-1 Receptor Agonists
  • Animals
  • Animals, Newborn
  • Atrial Natriuretic Factor (biosynthesis, genetics)
  • Boron Compounds (pharmacology)
  • Calcium (metabolism)
  • Calcium Signaling (drug effects)
  • Cells, Cultured
  • Heart Ventricles
  • Hypertrophy (chemically induced)
  • Inositol 1,4,5-Trisphosphate Receptors (physiology)
  • Leucine (metabolism)
  • Macrocyclic Compounds (pharmacology)
  • Myocytes, Cardiac (pathology)
  • Oxazoles (pharmacology)
  • Phenylephrine (pharmacology)
  • RNA, Messenger (biosynthesis, genetics)
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction

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