Title | Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Zhang, Y, Huang, Y, Cantalupo, A, Azevedo, PS, Siragusa, M, Bielawski, J, Giordano, FJ, Di Lorenzo, A |
Journal | JCI Insight |
Volume | 1 |
Issue | 5 |
Date Published | 2016 Apr 21 |
ISSN | 2379-3708 |
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 S1P receptor 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. |
DOI | 10.1172/jci.insight.85484 |
Alternate Journal | JCI Insight |
PubMed ID | 27158676 |
PubMed Central ID | PMC4855879 |
Grant List | R01 HL126913 / HL / NHLBI NIH HHS / United States |