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Aim:Intracellular Ca~(2+)plays pivotal roles in diverse cellular functions,includinggene transcription that underlies cardiac remodeling during stress responses.However,the role of inositol 1,4,5-trisphosphate receptors(IP_3Rs)in the media-tion of cardiac intracellular Ca~(2+)and hypertrophic growth remains elusive.Priorwork with neonatal rat ventricular myocytes suggests that activation of IP_3Rsmay be linked to α_1 adrenergic receptor(α_1AR)increased stereotyped Ca~(2+)sparkoccurrence and global Ca~(2+)oscillations.Thus,we hypothesized that Ca~(2+)releasethrough IP_3Rs was necessary for α_1AR-stimulated cardiac hypertrophy.Methods:We used myoinositol 1,4,5-trisphosphate hexakis(butyryloxymethyl)ester(IP_3BM),a membrane-permeant ester of IP_3,to activate IP_3Rs directly,and Fluo 4/AM tomeasure intracellular Ca~(2+)signaling.Results:IP_3BM(10μmol·L~(-1))mimicked theeffects of phenylephrine,a selective agonist of α_1AR,in increments in local Ca~(2+)spark release(especially in the perinuclear area)and global Ca~(2+)transientfrequencies.More importantly,IP_3R inhibitors,2-aminoethoxydiphenyl borateand Xestospongin C,abolished the IP_3BM-induced Ca~(2+)responses,and signifi-cantly suppressed α_1AR-induced cardiomyocyte hypertrophy assayed by cellsize,[~3H]leucine incorporation and atrial natriuretic factor gene expression,dur-ing sustained(48 h)phenylephrine stimulation.Conclusion:These results,therefore,provide cellular mechanisms that link IP_3R signaling to α_1AR-stimulatedgene expression and cardiomyocyte hypertrophy.
Aim: Intracellular Ca ~ (2+) 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 (IP_3Rs) in the media-tion of The results showed that the activation of IP_3Rsmay be linked to α_1 adrenergic receptor (α_1AR) increased stereotyped Ca ~ (2+) sparkoccurrence and global Ca ~ (2+) ) oscillations.Thus, we hypothesized that Ca 2+ releasethrough IP_3Rs was necessary forα_1AR-stimulated cardiac hypertrophy.Methods: We used myoinositol 1,4,5-trisphosphate hexakis (butyryloxymethyl) ester (IP_3BM), a membrane-permeant ester of IP_3, to activate IP_3Rs directly, and Fluo 4 / AM to measure intracellular Ca ~ (2 +) signaling.Results: IP_3BM (10μmol·L -1) mimicked the effects of phenylephrine, a selective agonist ofα_1AR, in increments in local Ca ~ (2+) spark release (especially in the perinuclear area) and global Ca 2+ transientfrequencies. Importantly, IP_3R inhibitors, 2-aminoethoxydiphenyl borate and Xestospongin C, abolished the IP_3BM-induced Ca 2+ responses, and signifi-cantly suppressed α_1AR-induced cardiomyocyte hypertrophy assayed by cellsize, [~ 3H] leucine incorporation and atrial natriuretic factor gene expression, dur-ing sustained (48 h) phenylephrine stimulation. Conlusion: These results, therefore, provide cellular mechanisms that link IP_3R signaling to α_1AR-stimulatedgene expression and cardiomyocyte hypertrophy.