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J Cell Biol. 2012 Nov 26;199(5):783-98. doi: 10.1083/jcb.201111095. Epub 2012 Nov 19.

Mutual antagonism between IP(3)RII and miRNA-133a regulates calcium signals and cardiac hypertrophy.

Author information

1
Babraham Institute, Babraham, Cambridge CB22 3AT, England, UK.

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.

PMID:
23166348
PMCID:
PMC3514786
DOI:
10.1083/jcb.201111095
[Indexed for MEDLINE]
Free PMC Article

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