MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy
Julie Halkein, … , Denise Hilfiker-Kleiner, Ingrid Struman
Julie Halkein, … , Denise Hilfiker-Kleiner, Ingrid Struman
Published April 24, 2013
Citation Information: J Clin Invest. 2013;123(5):2143-2154. https://doi.org/10.1172/JCI64365.
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Research Article

MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy

Abstract

Peripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy in previously healthy women. Although PPCM is driven in part by the 16-kDa N-terminal prolactin fragment (16K PRL), the underlying molecular mechanisms are poorly understood. We found that 16K PRL induced microRNA-146a (miR-146a) expression in ECs, which attenuated angiogenesis through downregulation of NRAS. 16K PRL stimulated the release of miR-146a–loaded exosomes from ECs. The exosomes were absorbed by cardiomyocytes, increasing miR-146a levels, which resulted in a subsequent decrease in metabolic activity and decreased expression of Erbb4, Notch1, and Irak1. Mice with cardiomyocyte-restricted Stat3 knockout (CKO mice) exhibited a PPCM-like phenotype and displayed increased cardiac miR-146a expression with coincident downregulation of Erbb4, Nras, Notch1, and Irak1. Blocking miR-146a with locked nucleic acids or antago-miRs attenuated PPCM in CKO mice without interrupting full-length prolactin signaling, as indicated by normal nursing activities. Finally, miR-146a was elevated in the plasma and hearts of PPCM patients, but not in patients with dilated cardiomyopathy. These results demonstrate that miR-146a is a downstream-mediator of 16K PRL that could potentially serve as a biomarker and therapeutic target for PPCM.

Authors

Julie Halkein, Sebastien P. Tabruyn, Melanie Ricke-Hoch, Arash Haghikia, Ngoc-Quynh-Nhu Nguyen, Michaela Scherr, Karolien Castermans, Ludovic Malvaux, Vincent Lambert, Marc Thiry, Karen Sliwa, Agnes Noel, Joseph A. Martial, Denise Hilfiker-Kleiner, Ingrid Struman

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Figure 6

Role of miR-146a in PPCM and proposed alternative treatment that maintains normal PRL functions.

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Role of miR-146a in PPCM and proposed alternative treatment that maintai...
(A) In PPCM patients, PRL is cleaved into 16K PRL, which (via NF-κB) increases miR-146a expression in ECs. By targeting NRAS, miR-146a reduces proliferation and viability in ECs and contributes to destruction of the cardiac microvasculature. miR-146a is released from ECs protected by the exosomes that fuse with cardiomyocytes, where miR-146a targets ERBB4 and impairs metabolism. (B and C) Proposed therapeutic options for PPCM management. (B) Blocking PRL completely by use of bromocriptine eliminates pathophysiological 16K PRL, but also nursing ability. (C) Use of anti-miR-146a in less severely affected patients may improve PPCM recovery, while keeping normal nursing functions.