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


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 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.


CONCLUSIONS
These results, therefore, provide cellular mechanisms that link IP3R signaling to alpha1AR-stimulated gene expression and cardiomyocyte hypertrophy.
Luo
Da-li
DL
Department of Pharmacology, School of Chemical Biology and Pharmaceutical Sciences, Capital University of Medical Sciences, Beijing 100069, China. luodl@bjmu.edu.cn
Gao
Jian
J
Lan
Xiao-mei
XM
Wang
Gang
G
Wei
Sheng
S
Xiao
Rui-ping
RP
Han
Qi-de
QD
D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D006352:Heart Ventricles; D006984:Hypertrophy / Q000139:chemically induced; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology*; D007930:Leucine / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000473:pathology*; D010080:Oxazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D058646:Adrenergic alpha-1 Receptor Agonists; D001896:Boron Compounds; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D012333:RNA, Messenger; C511704:xestospongin C; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; C109986:2-aminoethoxydiphenyl borate; D007930:Leucine; D002118:Calcium