RGD Reference Report - MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. - Rat Genome Database

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

Authors: Halkein, J  Tabruyn, SP  Ricke-Hoch, M  Haghikia, A  Nguyen, NQ  Scherr, M  Castermans, K  Malvaux, L  Lambert, V  Thiry, M  Sliwa, K  Noel, A  Martial, JA  Hilfiker-Kleiner, D  Struman, I 
Citation: Halkein J, etal., J Clin Invest. 2013 May 1;123(5):2143-54. doi: 10.1172/JCI64365. Epub 2013 Apr 24.
RGD ID: 7495791
Pubmed: PMID:23619365   (View Abstract at PubMed)
PMCID: PMC3638905   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI64365   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cardiomyopathy  ISOIrak1 (Mus musculus)7495791; 7495791mRNA:decreased expression:heart left ventricleRGD 
cardiomyopathy  IEP 7495791mRNA:decreased expression:heart left ventricleRGD 
cardiomyopathy  ISOStat3 (Mus musculus)7495791; 7495791 RGD 
cardiomyopathy  IMP 7495791 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Irak1  (interleukin-1 receptor-associated kinase 1)
Stat3  (signal transducer and activator of transcription 3)

Genes (Mus musculus)
Irak1  (interleukin-1 receptor-associated kinase 1)
Stat3  (signal transducer and activator of transcription 3)

Genes (Homo sapiens)
IRAK1  (interleukin 1 receptor associated kinase 1)
STAT3  (signal transducer and activator of transcription 3)


Additional Information