MicroRNA-1 Negatively Regulates Expression of the Hypertrophy-Associated Calmodulin and Mef2a Genes

Abstract

Calcium signaling is a central regulator of cardiomyocyte growth and function. Calmodulin is a critical mediator of calcium signals. Because the amount of calmodulin within cardiomyocytes is limiting, the precise control of calmodulin expression is important for the regulation of calcium signaling. In this study, we show for the first time that calmodulin levels are regulated posttranscriptionally in heart failure. The cardiomyocyterestricted microRNA miR-1 inhibited the translation of calmodulin-encoding mRNAs via highly conserved target sites within their 3 untranslated regions. In keeping with its effect on calmodulin expression, miR-1 downregulated calcium-calmodulin signaling through calcineurin to NFAT. miR-1 also negatively regulated the expression of Mef2a and Gata4, key transcription factors that mediate calcium-dependent changes in gene expression. Consistent with the downregulation of these hypertrophy-associated genes, miR-1 attenuated cardiomyocyte hypertrophy in cultured neonatal rat cardiomyocytes and in the intact adult heart. Our data indicate that miR-1 regulates cardiomyocyte growth responses by negatively regulating the calcium signaling components calmodulin, Mef2a, and Gata4.

MicroRNA and Its Role in Cardiovascular Disease

“…Calmodulin, Mef2a and Gata4 are the main calcium dependent transcription factors and miR-1 inhibits these transcription factors as shown by a study in a mice model [37]. miR-133 regulates transcription factors like RhoA, a GDP-GTP exchange protein, Cdc42 which are associated with cardiac hypertrophy and Nelf-A/WHSC2 related to cardiogenesis [34].…”

MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis

“…While circulating levels of miR‐1 and ‐133 are elevated, in patients with ischaemic cardiomyopathy or after MI, however, the expression levels of miR‐1 and ‐133 are diminished in diseased human heart 70, 82, 87, 90.…”

Many routes to the same destination: lessons from skeletal muscle development

“…The mechanisms of these effects include the ability of miR-1/206 to negatively regulate follistatin and utrophin, both of which retain myoblasts in an undifferentiated state (Rosenberg et al 2006). Other confirmed targets include DNA polymerase a (Kim et al 2006), HDAC4 , gap junction protein a1 (GJA1, also known as connexin43; Anderson et al 2006), calmodulin and MEF2A (Ikeda et al 2009), while miR-133 can target serum response factor (SRF) to maintain cells as proliferative myoblasts . This is far from an exhaustive list of targets of these microRNAs, and the true number of mRNAs regulated in this way remains unknown.…”