TY  - JOUR
AU  - Jabs, Markus
AU  - Rose, Adam J
AU  - Lehmann, Lorenz H
AU  - Taylor, Jacqueline
AU  - Moll, Iris
AU  - Sijmonsma, Tjeerd
AU  - Herberich, Stefanie E
AU  - Sauer, Sven W
AU  - Poschet, Gernot
AU  - Federico, Giuseppina
AU  - Mogler, Carolin
AU  - Weis, Eva-Maria
AU  - Augustin, Hellmut
AU  - Yan, Minhong
AU  - Gretz, Norbert
AU  - Schmid, Roland M
AU  - Adams, Ralf H
AU  - Gröne, Hermann-Joseph
AU  - Hell, Rüdiger
AU  - Okun, Jürgen G
AU  - Backs, Johannes
AU  - Nawroth, Peter P
AU  - Herzig, Stephan
AU  - Fischer, Andreas
TI  - Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart.
JO  - Circulation
VL  - 137
IS  - 24
SN  - 1524-4539
CY  - Philadelphia, Pa.
PB  - Lippincott, Williams & Wilkins
M1  - DKFZ-2018-00731
SP  - 2592 - 2608
PY  - 2018
AB  - Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function.Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice.Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-jκ-mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-jκ-deficient mice.This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.
LB  - PUB:(DE-HGF)16
C6  - pmid:29353241
DO  - DOI:10.1161/CIRCULATIONAHA.117.029733
UR  - https://inrepo02.dkfz.de/record/136031
ER  -