NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression

Abstract

Activation of NFAT (nuclear factor of activated T cells)-mediated hypertrophic signaling is a major regulatory response to hypertrophic stimuli. A recent study unveiled potential regulatory roles for microRNA-133a (miR-133a) in cardiac hypertrophy. To date, however, no connection has been made between miR-133a and NFAT signaling. In this study, we determined that NFATc4, a hypertrophy-associated mediator, is negatively regulated by miR-133a. Two conserved base-pairing sites between the NFATc4 3'-untranslated region (UTR) and miR-133a were verified. Mutation of these sites in the NFATc4 3'-UTR completely blocked the negative effect of miR-133a on NFATc4, suggesting that NFATc4 is a direct target for miR-133a regulation. Using a gain-of-function approach, we demonstrate that miR-133 significantly reduces the endogenous level of, as well as the hypertrophic stimulus-mediated increase in, NFATc4 gene expression. This latter effect of miR-133a on NFATc4 gene expression was coincided with an attenuated cardiomyocyte hypertrophy induced by an alpha-adrenergic receptor agonist. Conversely, cells treated with miR-133a inhibitor resulted in an increase in NFATc4 expression level. Application of miR-133a had no apparent effect on NFATc4 nuclear localization. We conclude that the negative regulation of NFATc4 expression contributes to miR-133a-mediated hypertrophic repression.

A Cardiac-enriched MicroRNA, miR-378, Blocks Cardiac Hypertrophy by Targeting Ras Signaling

“…miR-9 directly targets myocardin and interferes with the nuclear activity of NFAT (69). miR-133a inhibits hypertrophy by direct targeting of calcineurin (68), NFAT (66), and Cdc42 and RhoA (63), miR-1 targets twinfilin-1 (70), and calmodulinmediated hypertrophic signaling (64,71). Genetic deficiency of miR-133a results in extensive fibrosis, impaired cardiac function, and pathological remodeling (72).…”

“…Overexpression of these miRNAs enhances hypertrophic growth and their inhibition confers resistance to cardiac stress (51, 54 -61). Among the anti-hypertrophic miRNAs, miR-98/let-7 regulates cardiac hypertrophy indirectly via thioredoxin (62), the other three miRNAs (miR-9, miR-1, and miR-133) could directly inhibit response of cardiomyocytes to hypertrophic stimuli (53,(63)(64)(65)(66)(67)(68)(69). Expression of these three miRNAs is down-regulated by hypertrophy agonists and their overexpression diminished the hypertrophic response.…”

MicroRNA-124 Suppresses the Transactivation of Nuclear Factor of Activated T Cells by Targeting Multiple Genes and Inhibits the Proliferation of Pulmonary Artery Smooth Muscle Cells

“…Although accumulating data have suggested that miRNAs function in regulating SMC proliferation and differentiation (23)(24)(25), whether this effect is achieved by regulating NFAT signaling pathway through miRNAs is still unclear. In this study, we performed a high throughput screening by using an in-house-made miRNA expression library and NFAT luciferase reporter system.…”

Myocardial calcium signaling in physiology and disease

“…Interestingly, miR-214 was reported to target and repress NCX1 and protects cardiomyocytes from Ca 2+ -induced cell death during ischemia/reperfusion injury. 177 In addition, miR-133a, which is bi-cistronically clustered with miR-1, was shown to have a strong effect on Ca 2+ signaling pathways in cardiomyocytes by targeting calcineurin, 178 NFATc4, 179 and IP 3 R2. 180 The latter study also showed that IP 3 -induced Ca 2+ release significantly contributes, in a feed-forward mechanism, to the down-regulation of miR-133a during hypertrophy and accentuation of pathological remodeling.…”