Endothelial Cell GATA2 Modulates the Cardiomyocyte Stress Response through the Regulation of Two Long Non-Coding RNAs

SIMPLE SUMMARY: Endothelial cells constitute the inner layer of blood vessels and they are the main constituent of the capillaries, which are the smallest blood vessels of the body that deliver nutrients and oxygen to the different organs. The heart contains an especially high number of capillaries in order to provide enough energy for the blood pumping activity of the cardiac muscle cells. While the contribution of these muscle cells for the development of heart failure has been investigated for decades, the role of endothelial cells in this deadly disease remains largely unclear. We showed in this study that elimination of the transcription factor GATA2 from endothelial cells leads to aggravated cardiac failure in mice with experimental transverse aortic constriction (TAC), which is a model for pressure overload of the heart as it occurs in longstanding arterial hypertension or narrowing of the aortic valve. We found that lack of GATA2 did not change the number of capillaries in the heart, but rather led to secretion of two so far unknown long non-coding RNAs (i.e. RNAs that do not code for proteins) from endothelial cells, which might trigger heart failure by acting on stress responsiveness of cardiac muscle cells. ABSTRACT: Capillary endothelial cells modulate myocardial growth and function during pathological stress, but it is unknown how and whether this contributes to the development of heart failure. We found that the endothelial cell transcription factor GATA2 is downregulated in human failing myocardium. Endothelial GATA2 knock-out (G2-EC-KO) mice develop heart failure and defective myocardial signal transduction during pressure overload, indicating that the GATA2 downregulation is maladaptive. Heart failure and perturbed signaling in G2-EC-KO mice could be induced by strong upregulation of two unknown, endothelial cell-derived long non-coding (lnc) RNAs (AK037972, AK038629, termed here GADLOR1 and 2). Mechanistically, the GADLOR1/2 lncRNAs transfer from endothelial cells to cardiomyocytes, where they block stress-induced signalling. Thereby, lncRNAs can contribute to disease as paracrine effectors of signal transduction and therefore might serve as therapeutic targets in the future.