In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 121, No. suppl_1 ( 2017-07-21)
Abstract:
Capillary endothelial cells influence myocardial growth and function during pathological stress by releasing paracrine factors. We found that the transcription factor GATA2 is suppressed in cardiac endothelial cells by mechanical stimuli, and that GATA2 is downregulated in human failing hearts. To investigate the functional consequence of reduced endothelial GATA2 expression, we exposed endothelial cell specific, inducible GATA2 knock-out (G2-EC-KO) or wild-type (WT) mice to pressure overload through transverse aortic constriction (TAC). G2-EC-KO mice developed aggravated heart failure after TAC, but not enhanced fibrosis or capillary rarefaction. Investigation of stress signaling pathways revealed a prominent activation of p38 MAP kinases and Akt in cardiomyocytes after TAC only in WT mice, but not in G2-EC-KO mice, which in addition exerted increased calcineurin/NFAT activation. Transcriptional profiling revealed a strong upregulation of two distinct previously unknown long non-coding (lnc) RNAs in cardiac endothelial cells from G2-EC-KO mice, which we termed GADLOR1 and GADLOR2 and which were also induced in human failing hearts. Both RNAs were also induced in cultured cardiac endothelial cells in vitro after ablation of GATA2 and were found to be secreted within extracellular vesicles. Isolated cardiomyocytes incubated with extracellular vesicles from GATA2 depleted endothelial cells efficiently incorporated GADLOR1 and 2. Uptake of GADLORs by cardiomyocytes led to a profound reduction of p38 MAPK and Akt activation. Proteomic screening revealed that GADLOR1/2 bind the Ras-like protein TC21 in cardiomyocytes and block downstream signaling by preventing TC21 binding to its target PI3K. Application of both lncRNAs to the mouse myocardium by exosomal gene-transfer triggered aggravated cardiac dysfunction and disturbed stress signaling, while in turn inhibition of GADLOR1/2 by specific GapmeRs rescued stress signaling and cardiac dysfunction in G2-EC-KO mice during TAC. In summary, GATA2 protects the heart during pressure overload by suppressing the endothelial release of two long non-coding RNAs, which interfere with stress signaling in cardiomyocytes and ultimately induce heart failure.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.121.suppl_1.247
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
1467838-X
