P328Does cardiomyocyte specific deletion of plasma membrane calcium ATPase 1 lead to altered microRNA expression in heart failure?

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MicroRNAs are newly discovered small non-coding RNAs that can regulate hypertrophic gene expression at the post-transcriptional level through targeted mRNA ‘silencing’ in heart failure. Abnormal Ca2+ handling impairs cardiac function and our research group has shown that deletion of the calcium extrusion pump, plasma membrane Ca2+ ATPase1 (PMCA1), leads to dilated cardiomyopathy and heart failure. This study aims to determine whether deletion of PMCA1 leads to altered microRNA expression in heart failure.

Methods and Results

PMCA1 cardiomyocyte-specific knockout (PMCA1cko) mice were generated using Cre/LoxP technology. A microarray plate revealed a number of microRNA changes in PMCA1cko mice (n=5) compared to PMCA1loxp/loxp (controls) (n=7)which, by reverse transcription and qPCR, confirmed a marked down-regulation (p < 0.05) of miRNAs let7e (75%), let7i(50%), 101(76%), 101a(61%), and 93(57%). PMCA1cko and PMCA1loxp/loxp mice were subjected to haemodynamic stress by transverse aortic constriction (TAC) inducing cardiac hypertrophy. After TAC, PMCA1loxp/loxp mice demonstrated a downregulation of mir-101a by 50% (p=0.06) compared to sham operated PMCA1loxp/loxp mice but there was an overexpression by 61% ( < 0.05) in the PMCA1cko mice (n=3). Rcan1.4, a marker of NFAT activity, was upregulated ( > 300%) in PMCA1cko mice (n=7) under basal conditions.


Deletion of PMCA1 has been shown to directly or indirectly regulate transcription of microRNAs let7e, 7i, 101, 101a and 93, whilst under pathological hypertrophic conditions, deletion of PMCA1 leads to upregulation of miR101 and 101a. Initial studies suggest MicroRNAs 101 and 101a may regulate pathological hypertrophy through suppression of the calcineurin-NFAT pathway, one of the most well characterised pathways in heart failure.

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