title: Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload.
abstract: We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular function by inhibiting the rate-limiting enzyme, serine palmitoyltransferase (SPT), in de novo sphingolipid biosynthesis. Here, we show that endothelium-derived sphingolipids, particularly sphingosine-1-phosphate (S1P), protect the heart from inflammation, fibrosis, and dysfunction following pressure overload and that Nogo-B regulates this paracrine process. SPT activity is upregulated in banded hearts in vivo as well as in TNF-α-activated endothelium in vitro, and loss of Nogo removes the brake on SPT, increasing local S1P production. Hence, mice lacking Nogo-B, systemically or specifically in the endothelium, are resistant to the onset of pathological cardiac hypertrophy. Furthermore, pharmacological inhibition of SPT with myriocin restores permeability, inflammation, and heart dysfunction in Nogo-A/B-deficient mice to WT levels, whereas SEW2871, an S1P1receptor agonist, prevents myocardial permeability, inflammation, and dysfunction in WT banded mice. Our study identifies a critical role of endothelial sphingolipid biosynthesis and its regulation by Nogo-B in the development of pathological cardiac hypertrophy and proposes a potential therapeutic target for the attenuation or reversal of this clinical condition.
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, and Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Cantalupo
authors.affiliation: Department of Internal Medicine, Botucatu Medical School, University of Estadual Paulista, Botucatu, São Paulo, Brazil.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Azevedo
authors.affiliation: Center for Molecular Medicine, Institute for Vascular Signalling, Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Mauro
authors.initials: M
authors.lastname: Siragusa
authors.affiliation: Lipidomics Mass Spectrometry Facility, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, and Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Giordano
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.
authors.forename: Annarita
authors.initials: A
authors.lastname: Di Lorenzo