Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload
Yi Zhang, … , Frank J. Giordano, Annarita Di Lorenzo
Yi Zhang, … , Frank J. Giordano, Annarita Di Lorenzo
Published April 21, 2016
Citation Information: JCI Insight. 2016;1(5):e85484. https://doi.org/10.1172/jci.insight.85484.
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Research Article Cardiology Vascular biology

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 S1P1 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.

Authors

Yi Zhang, Yan Huang, Anna Cantalupo, Paula S. Azevedo, Mauro Siragusa, Jacek Bielawski, Frank J. Giordano, Annarita Di Lorenzo

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Figure 7

Endothelial Nogo-B regulates de novo synthesis of sphingolipid to affect cardiac pathogenesis through SPT/S1P signaling.

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Endothelial Nogo-B regulates de novo synthesis of sphingolipid to affect...
(A) Experimental design related to B and C: WT and Nogo-A/B–deficient mice were i.p. injected with a selective inhibitor of SPT, myriocin (0.3 mg/kg), or vehicle (0.4% fatty acid–free BSA) at the indicated time points. (B) Myocardial permeability assessed 24 hours after surgery by quantifying Evans Blue extravasated into sham-operated or banded WT and Nogo-A/B–deficient hearts. n ≥ 6/group. (C) Inflammation was assessed at 3 days after surgery in WT and Nogo-A/B–deficient mice treated with myriocin or vehicle by immunostaining of CD45 in heart sections and (D) quantification. Scale bar: 100 μm. n ≥ 6 mice/group. Serial echocardiographic analyses of transverse aortic constriction–operated (TAC-operated) WT and Nogo-A/B–deficient mice treated with myriocin (0.3 mg/kg) or vehicle. The parameters measured were (E) left ventricle (LV) end-diastolic diameter (LVDd), (F) LV end systolic diameter (LVDs), and (G) LV fractional shortening (FS). n ≥ 7 mice/vehicle group; n = 7–11 mice/myriocin group. (H) Experimental design: WT mice were i.p. injected with an agonist of S1P1 receptor, SEW2871 (3 mg/kg), or vehicle (DMSO) as shown. (I) Images and (J) quantification of immunohistochemical staining of CD45 in sections of hearts from SEW2871- and vehicle-treated mice 3 days after TAC. n ≥ 7. Scale bar: 100 μm. (K) Serial echocardiographic analyses of TAC-operated mice treated with SEW2871 (3 mg/kg) or vehicle as indicated in H. n = 5 vehicle-treated WT mice; n = 9 SEW2871-treated mice. (L) Analysis of heart weight/tibia length ratios (heart/TL) of hearts from SEW2871- or vehicle-treated mice at 3 months after TAC. n ≥ 5/group. Data are expressed as mean ± SEM. **P < 0.01, ***P < 0.001, #P < 0.05, ###P < 0.001 for myoricin- versus vehicle-treated Nogo-A/B–deficient mice. Statistical significance was evaluated with (B and D) 1-way ANOVA followed by Tukey’s multiple comparison test, (E–G and K) 2-way ANOVA followed by Tukey’s multiple comparison test, and (J and L) unpaired t test.