Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
Sci Signal. 2017 Aug 15;10(492):eaal2722. doi: 10.1126/scisignal.aal2722.
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 (ApoMHDL), 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.
内皮功能障碍是血管疾病的一个标志，可被血浆高密度脂蛋白（HDL）修复。然而，HDL 丰度的普遍增加并没有益处，这表明特定的 HDL 种类介导保护作用。载脂蛋白 M 包含的高密度脂蛋白（ApoMHDL）携带生物活性脂质鞘氨醇 1-磷酸（S1P），通过激活 G 蛋白偶联 S1P 受体来促进内皮功能。此外，HDL 结合的 S1P 在几种炎症、代谢和血管疾病中是有限的。我们报告了一种 S1P 的可溶性载体 ApoM-Fc 的开发，它以持续的方式激活 S1P 受体并促进内皮功能。相比之下，ApoM-Fc 并没有调节循环淋巴细胞的数量，这表明它特异性地激活了内皮 S1P 受体。ApoM-Fc 的给药降低了高血压小鼠的血压，减轻了缺血/再灌注损伤后的心肌损伤，并减少了大脑中动脉闭塞模型中风的脑梗死体积。我们的概念验证研究表明，ApoM-Fc 对内皮 S1P 受体的选择性和持续靶向可能是血管疾病的一种可行的治疗策略。
