title: 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.affiliation: Unit of Molecular Biology and Genetic Engineering, GIGA, University of Liège, Liège, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Halkein
authors.forename: Sebastien P
authors.initials: SP
authors.lastname: Tabruyn
authors.forename: Melanie
authors.initials: M
authors.lastname: Ricke-Hoch
authors.forename: Arash
authors.initials: A
authors.lastname: Haghikia
authors.forename: Ngoc-Quynh-Nhu
authors.initials: NQ
authors.lastname: Nguyen
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Karolien
authors.initials: K
authors.lastname: Castermans
authors.forename: Ludovic
authors.initials: L
authors.lastname: Malvaux
authors.forename: Vincent
authors.initials: V
authors.lastname: Lambert
authors.forename: Marc
authors.initials: M
authors.lastname: Thiry
authors.forename: Karen
authors.initials: K
authors.lastname: Sliwa
authors.forename: Agnes
authors.initials: A
authors.lastname: Noel
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Martial
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Ingrid
authors.initials: I
authors.lastname: Struman
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D009202:Cardiomyopathies / Q000097:blood* / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D009389:Neovascularization, Pathologic; D058725:Peripartum Period; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000097:blood* / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; C542542:MIRN146 microRNA, human; C554180:MIRN146 microRNA, rat; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D011388:Prolactin