Editors' ChoiceCardiovascular Disease

A miR-aculous Advance for a Rare Heart Disorder

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Science Translational Medicine  22 May 2013:
Vol. 5, Issue 186, pp. 186ec85
DOI: 10.1126/scitranslmed.3006596

Peripartum cardiomyopathy (PPCM) is a relatively rare disorder characterized by acute reduction in the mechanical performance of the heart in mothers in the final month of pregnancy or within the first 5 weeks after delivery. Although the exact etiology of PPCM is not known, there is growing evidence that abnormal processing of the pregnancy-related hormone, prolactin, into a proapoptotic 16-kD isoform could play a causal role in PPCM. Supporting this hypothesis are small studies demonstrating that inhibition of prolactin with the drug bromocriptine can attenuate or even reverse PPCM in certain individuals. However, because of prolactin’s essential role in nursing, bromocriptine is contraindicated in mothers who develop PPCM but wish to breast-feed their infants. In a new study, Halkein et al. report a direct mechanistic link between expression of a microRNA (miRNA) called miR-146a and PPCM that provides new insights into this disease and potential new therapeutic options.

The authors first identified miRNAs that were up-regulated by the 16-kD prolactin isoform in cultured human endothelial cells. They next demonstrated that miR-146a can be loaded into exosomes by human endothelial cells and that these exosomes can be absorbed by rat cardiomyocytes. The delivery of miR-146a to mouse cardiomyocytes caused metabolic changes through altered expression of several downstream genes. The authors further demonstrated that blocking miR-146a activity with antisense miRNAs attenuated the decrease in cardiac performance in a genetic mouse model of PPCM, but without impairing prolactin function (the ability of the mice to nurse). Last, the authors found that miR-146a was elevated in the plasma of patients with PPCM and was reduced in those who had favorable responses to bromocriptine treatment.

Although preliminary, these results lay the foundation for a new way to diagnose and treat patients with PPCM that avoids the deleterious effects of bromocriptine treatment on nursing mothers. Patients with PPCM could be screened for elevated concentrations of miR-146a and then could be treated with miRNAs that antagonize miR-146a. This new approach would allow nursing mothers with PPCM to continue to nurse while receiving a potentially life-saving therapy.

J. Halkein et al., MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J. Clin. Invest. 123, 2143–2154 (2013). [Full Text]

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