muromonab-cd3 and 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.

Topics: Adrenergic alpha-1 Receptor Agonists; Animals; Animals, Newborn; Atrial Natriuretic Factor; Boron Compounds; Calcium; Calcium Signaling; Cells, Cultured; Heart Ventricles; Hypertrophy; Inositol 1,4,5-Trisphosphate Receptors; Leucine; Macrocyclic Compounds; Myocytes, Cardiac; Oxazoles; Phenylephrine; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction