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.

Sphingolipid De Novo Biosynthesis: A Rheostat of Cardiovascular Homeostasis

“…However, systemic loss of SPT is genetically lethal [32], while CM-specific deficiency of SPT leads to cardiac fibrosis and dysfunction, despite the reduction in ceramide [99]. In agreement with these findings, the inhibition of SPT by myriocin restores the PCH in Nogo-A/B-deficient mice following pressure overload[95], supporting a cardioprotective role of SPT. Apparently contradictory, these lines of evidence suggest that 1) SL are necessary to maintain cardiovascular homeostasis; 2) SL levels need to be contained in a rather finite physiological window; 3) SL de novo biosynthesis has to be tightly regulated because an exaggerated production of SL, such as during metabolic diseases, triggers derangement of cardiovascular functions.…”

“…A recent study from Zhang et al . demonstrated that endothelial S1P protects the heart from inflammation, fibrosis and loss of function during chronic pressure overload through the activation of the endothelial S1P-S1PR1-eNOS autocrine signaling[95]. In the heart Nogo-B, identified as inhibitor of SPT (Figure 1), is expressed only in blood vessels and atria but not in ventricular CM.…”

“…Considering the vicinity of capillaries and myocytes, vascular-derived SL, particularly S1P, could also directly impact CM biology. Interestingly, SEW2871 protect the heart from PCH triggered by chronic pressure overload, supporting a cardioprotective role of S1PR1 signaling [95]. …”

“…The upregulation of sphingolipid production, particularly of S1P, and S1P signaling exert protective functions in hypertension [26], PCH [95], atherosclerosis [51] and vascular barrier maintenance [37, 42, 43, 95] mainly though the receptor S1PR1.…”

Nogo-B Promotes Angiogenesis in Proliferative Diabetic Retinopathy via VEGF/PI3K/Akt Pathway in an Autocrine Manner

“…Previous studies reported that Nogo-B was associated with vascular remodeling upon vascular injury [21]. More recently, it was demonstrated that Nogo-B regulated sphingolipid homeostasis to control blood pressure [22, 23]. However, little attention was paid to the function of Nogo-B in diabetic vascular pathology especially in PDR.…”