An engineered S1P chaperone attenuates hypertension and ischemic injury

Abstract

Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M–containing HDL (ApoM+HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein–coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases. We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc could be a viable therapeutic strategy in vascular diseases.

Sphingosine 1‐Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex–Induced Vascular Injury

“…A novel engineered S1P chaperone, ApoM-Fc loaded with S1P- [19], was used in vitro (10 μg/ml) and in vivo (4 mg/kg IP). Human recombinant C5a (R&D Systems; 100 ng/ml) was used to activate PMNs.…”

“…Although vascular injury is a critical pathophysiologic component of the RAR, pharmacologic targeting of the EC barrier has not been studied. In this study, we show that S1P 1 agonists, including a novel engineered S1P chaperone - ApoM-Fc [19], prevent barrier dysfunction in response to activated neutrophil-induced injury in vitro and diminish neutrophil transmigration and red blood cell (RBC) extravasation in vivo. These data support a novel approach to limiting inflammation by enhancing EC barrier integrity and thus, have implications for the treatment of patients with IC-mediated injury.…”

Arteriovenous Sphingosine-1-Phosphate Differences Across Selected Organs of the Rat

“…The fact that this effect resulted almost exclusively from the decrease in S1P and SA1P content in LPDP, whereas the concentration of HDL-associated sphingoid base-1-phosphates remained stable, is also consistent with this hypothesis. It was found that ApoM-bound S1P has a much longer half-life in vivo compared to albumin-bound S1P [13, 16]. In addition, the rate of degradation of HDL-bound S1P by the vascular ECs was reported to be markedly lower compared to the albumin-associated S1P [30].…”

“…HDL-associated S1P was also shown to exert anti-inflammatory and antiatherosclerotic effects in the vascular endothelium [42]. In addition, HDL-bound S1P was recently found to promote regeneration and suppress fibrosis in the liver, as well as to attenuate hypertension and ischemic injury [13, 43]. …”

“…Interestingly, the type of carrier strongly affects properties of circulating S1P. HDL-bound S1P is characterized by greater biological activity and much longer half-life compared to albumin-associated S1P [13-16]. …”