Necessary Role of Ceramides in the Human Microvascular Endothelium During Health and Disease.
Necessary Role of Ceramides in the Human Microvascular Endothelium During Health and Disease.
复制标题
神经酰胺在健康和疾病期间人体微血管内皮细胞中的必要作用。
DOI：
10.1161/circresaha.123.323445
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发表时间：
2024-01-05
影响因子：
20.1
通讯作者：
Freed, Julie K.
中科院分区：
文献类型：
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作者：
Senthilkumar, Gopika;Katunaric, Boran;Zirgibel, Zachary;Lindemer, Brian;Jaramillo-Torres, Maria J.;Bordas-Murphy, Henry;Schulz, Mary E.;Pearson, Paul J.;Freed, Julie K.
血浆神经酰胺水平升高和微血管功能障碍均可独立预测不良心脏事件。尽管已知神经酰胺对微血管系统有不利影响，但有证据表明，剪切敏感性神经酰胺形成酶NSmase（中性鞘磷脂酶）的激活可促进血管保护性一氧化氮（NO）的形成。在这里，我们探讨了一个新的假设，急性神经酰胺形成通过NSmase是必要的，以维持人类微血管内皮细胞内的NO信号。我们进一步定义了神经酰胺发挥有益作用的机制，并识别了健康成人（非冠状动脉疾病[CAD]）和诊断为CAD的患者的小动脉之间的关键机制差异。从丢弃的手术脂肪组织（n=166）解剖人小动脉，并评估血管对流动和C2-神经酰胺的反应性。剪切诱导的NO和线粒体过氧化氢（H2 O2）的生产在小动脉中使用荧光显微镜进行测量。在分离的人脐静脉内皮细胞中评估H2 O2荧光。抑制NSmase在其他健康成人的小动脉诱导开关从NO到NOX-2（NADPH氧化酶2）依赖H2 O2介导的流量诱导的扩张。1-磷酸鞘氨醇（S1 P）治疗可预防内皮功能障碍，C2-神经酰胺和S1 P受体1（S1 PR 1）激动剂可部分预防内皮功能障碍; S1 P/S1 PR 1信号传导轴的抑制通过NOX-2诱导内皮功能障碍。神经酰胺增加了非CAD成人小动脉中NO的产生，这种作用随着S1 P/S1 PR 1/S1 P受体3信号传导的抑制而减弱。在CAD患者的小动脉中，NSmase的抑制损害了诱导线粒体H2 O2产生并随后扩张流动的整体能力，外源性S1 P不能恢复这种作用。急性神经酰胺管理CAD患者的小动脉促进H2 O2，而不是NO的生产，一种依赖于S1 P-受体3信号的效果。这些数据表明，尽管健康和疾病之间的下游信号传导不同，但NS酶介导的神经酰胺形成对于人类微血管内皮的正常功能是必要的。旨在显著降低神经酰胺形成的治疗策略可能对微血管系统有害。
Elevated plasma ceramides and microvascular dysfunction both independently predict adverse cardiac events. Despite the known detrimental effects of ceramide on the microvasculature, evidence suggests that activation of the shear-sensitive, ceramide-forming enzyme NSmase (neutral sphingomyelinase) elicits formation of vasoprotective nitric oxide (NO). Here, we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults (non–coronary artery disease [CAD]) and patients diagnosed with CAD. Human arterioles were dissected from discarded surgical adipose tissue (n=166), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO and mitochondrial hydrogen peroxide (H2O2) production were measured in arterioles using fluorescence microscopy. H2O2 fluorescence was assessed in isolated human umbilical vein endothelial cells. Inhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to NOX-2 (NADPH-oxidase 2)–dependent H2O2-mediated flow-induced dilation. Endothelial dysfunction was prevented by treatment with sphingosine-1-phosphate (S1P) and partially prevented by C2-ceramide and an agonist of S1P-receptor 1 (S1PR1); the inhibition of the S1P/S1PR1 signaling axis induced endothelial dysfunction via NOX-2. Ceramide increased NO production in arterioles from non-CAD adults, an effect that was diminished with inhibition of S1P/S1PR1/S1P-receptor 3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired the overall ability to induce mitochondrial H2O2 production and subsequently dilate to flow, an effect not restored with exogenous S1P. Acute ceramide administration to arterioles from patients with CAD promoted H2O2 as opposed to NO production, an effect dependent on S1P-receptor 3 signaling. These data suggest that despite differential downstream signaling between health and disease, NSmase-mediated ceramide formation is necessary for proper functioning of the human microvascular endothelium. Therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.