[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Halkein, Julie ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Tabruyn, Sebastien P.
Ricke-Hoch, Melanie
Haghikia, Arash
Nguyen, Ngoc-Quynh-Nhu
Scherr, Michaela
Castermans, Karolien
Malvaux, Ludovic
Lambert, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Ophtalmologie
Thiry, Marc ; Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire
Sliwa, Karen
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Martial, Joseph ; Université de Liège - ULiège > Département des sciences de la vie > Département des sciences de la vie
Hilfiker-Kleiner, Denise
Struman, Ingrid ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
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