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 (miR146a) 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 miR146a 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.

Cardiovascular diseases are a leading cause of morbidity and mortality in Western societies. It is now well established that microRNAs (miRNAs) are determinant regulators in various medical conditions including cardiovascular diseases. The recent discovery that miRNAs, while associated with different carriers, can be exported out of the cell, has triggered a renewed interest to analyze the potential to use extracellular miRNAs as tools for diagnostic and therapeutic studies. Circulating miRNAs in biological fluids present a technological advantage compared to current diagnostic tools by virtue of their remarkable stability and relative ease of detection rendering them ideal tools for non-invasive and rapid diagnosis. Extracellular miRNAs also represent a novel form of inter-cellular communication by transferring genetic information from a donor cell to a recipient cell. This review briefly summarizes recent insights in the origin, function and diagnostic potential of extracellular miRNAs by focusing on a select number of cardiovascular diseases.

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Insight miR-223 plays a remarkably modest role in thrombopoiesis and platelet function does not depend upon miR-223

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While cardiomyocytes (CMs) have been the main subject of extensive research, the role of other cardiac cell types, such as fibroblasts and endothelial cells (ECs), received considerable less attention in the pathogenesis of heart failure (HF). MiRNAs have recently emerged as mediators of paracrine signaling by being selectively incorporated in exosomes and exchanged between different cell types. The aim of our study is to investigate a potential paracrine miRNA crosstalk between CMs and cardiac ECs and assess the consequences of such miRNA transfer for cardiac vascular remodeling under pathological conditions. We isolated and characterized exosomes from CMs at baseline or after pathological stimulation with phenylephrine and isoproterenol. Although baseline and stressed CMs secrete miRNA-enriched exosomes at similar rates, comparative analysis of extracellular vesicles from both conditions revealed differential miRNA levels, with miR-200c-3p being highly enriched under stress conditions. Direct transfection of ECs with miR-200c-3p precursor molecules or indirect overexpression through transwell co-culture with stimulated CMs leads to diminished angiogenesis reflected by reduced capacity of ECs to proliferate, migrate, and form tubes. This effect was abrogated when we treated CMs with GW4869, an inhibitor of exosomal biogenesis and release. Next, we tested in vivo two doses of specific miR-200c-3p antagomir, Cy3 labelled, to assess specific target of ECs. FACS analysis on cardiac cells derived from the injected mice, confirmed that a low antagomir dose targets ECs whereas, the high dose of antagomir targets all different cardiac cell types. Moreover, when we treated mice subjected transverse aortic constriction (TAC)-induced cardiac pressure overload with miR-200c-3p antagomir, the animals developed a milder hypertrophic phenotype, smaller fibrotic areas, higher amount of capillaries and preserved cardiac ejection fraction, when compared to untreated pressure overloaded mice. Altogether, our results showing exosomal transfer of miR-200c-3p from CMs to ECs indicate the importance of cardiac intercellular communication in the pathophysiology of HF and identify a potential new therapeutic target for intervention strategies.