Exosome absorption


Peripartum cardiomyopathy (PPCM) is a deterioration in cardiac function that occurs in pregnant women during the last month or in the months following their pregnancy. This disorder can occur in women with no prior history of heart disease and the causes are not well understood. Julie Halkein and colleagues identified a molecule, miR-146a, that can serve as a biomarker for peripartum cardiomyopathy. Halkein and colleagues found that expression of miR-146a was induced by the nursing hormone prolactin and that miR-146a was elevated in the serum of pregnant women who later developed PPCM. Prolactin acts directly on the endothelial cells that line blood vessels, inhibiting migration and inducing cell death. The endothelial cells release exosomes that contain miR-146a into the blood and surrounding environment. These miR-146a-loaded exosomes are absorbed by both endothelial cells and cardiomyocytes, which form the heart muscle. The accompanying image is an electron micrograph of neonatal rat cardiomyocytes absorbing miR-146a exosomes. miR-146a blocked the formation of new blood vessels (angiogenesis) and impaired the metabolism and function of cardiomyocytes. These findings identify key pathological mechanisms and indicate that miR-146a could serve as a biomarker for PPCM.

Published April 24, 2013, by Jillian Hurst

Related articles

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.
View: Text | PDF
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

×
Advertisement