Abstract 13824: Impact of the Transcription Factor GATA2 in Endothelial Cells on the Development of Heart Failure Through the Regulation of Two Secreted Long Non-Coding RNAs
Background: It was proposed that capillary endothelial cells secrete paracrine factors to protect cardiomyocytes during hemodynamic overload. Here, we hypothesize that the endothelial cell transcription factor GATA2, which is activated by mechanical stimuli, might be a central regulator of the protective paracrine response during cardiac pressure overload.
Methods and Results: In order to test this, we exposed endothelial cell specific, tamoxifen inducible GATA2 knock-out (G2-EC-KO) or wild-type (WT) mice to pressure overload by inducing a transverse aortic constriction (TAC). Two weeks after surgery, there was no difference in sham operated mice of both genotypes, but G2-EC-KO mice after TAC displayed severely aggravated cardiac hypertrophy, increased pulmonary congestion and decreased cardiac function, while no enhanced fibrosis was detected. Investigation of stress signalling 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 prominent upregulation (50 to 70-fold) of two distinct previously unknown long non-coding (lnc) RNAs (lnc37 and lnc38) in cardiac endothelial cells from G2-EC-KO versus WT mice. Interestingly, both RNAs were also induced in cultured cardiac endothelial cells in vitro after ablation of GATA2 and were found to be secreted into the supernatant. Isolated cardiomyocytes incubated with supernatant from GATA2 depleted endothelial cells efficiently incorporated lnc37 and 38. Uptake of lnc37/38 by cardiomyocytes led to a profound reduction of p38 MAPK and Akt activation in response to phenylephrine in these cells. Finally, application of both lnc RNAs to the myocardium of WT mice by exosomal gene-transfer triggered aggravated cardiac dysfunction and disturbed stress dependent signalling (decreased Akt, p38 and increased calcineurin/NFAT) after TAC.
Conclusions: The endothelial transcription factor GATA2 protects the heart during pressure overload, most likely by suppressing the release of two long non-coding RNAs from endothelial cells, which interfere with stress signalling in cardiomyocytes and induce heart failure.
Author Disclosures: N. Froese: None. M. Szaroszyk: None. C. Napp: None. M. Korf-Klingebiel: None. D. Hilfiker-Kleiner: None. S.A. Camper: None. J.D. Molkentin: None. K.C. Wollert: None. J. Bauersachs: None. J. Heineke: None.
- © 2014 by American Heart Association, Inc.