title: Mutual antagonism between IP(3)RII and miRNA-133a regulates calcium signals and cardiac hypertrophy.
abstract: Inositol 1,4,5'-triphosphate receptor II (IP(3)RII) calcium channel expression is increased in both hypertrophic failing human myocardium and experimentally induced models of the disease. The ectopic calcium released from these receptors induces pro-hypertrophic gene expression and may promote arrhythmias. Here, we show that IP(3)RII expression was constitutively restrained by the muscle-specific miRNA, miR-133a. During the hypertrophic response to pressure overload or neurohormonal stimuli, miR-133a down-regulation permitted IP(3)RII levels to increase, instigating pro-hypertrophic calcium signaling and concomitant pathological remodeling. Using a combination of in vivo and in vitro approaches, we demonstrated that IP(3)-induced calcium release (IICR) initiated the hypertrophy-associated decrease in miR-133a. In this manner, hypertrophic stimuli that engage IICR set a feed-forward mechanism in motion whereby IICR decreased miR-133a expression, further augmenting IP(3)RII levels and therefore pro-hypertrophic calcium release. Consequently, IICR can be considered as both an initiating event and a driving force for pathological remodeling.
authors.affiliation: Babraham Institute, Babraham, Cambridge CB22 3AT, England, UK.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Drawnel
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wachten
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Marjorie
authors.initials: M
authors.lastname: Maillet
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.forename: Fredrik
authors.initials: F
authors.lastname: Swift
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.forename: Hanneke
authors.initials: H
authors.lastname: Okkenhaug
authors.forename: Simon R
authors.initials: SR
authors.lastname: Andrews
authors.forename: Martin D
authors.initials: MD
authors.lastname: Bootman
authors.forename: H Llewelyn
authors.initials: HL
authors.lastname: Roderick
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse