BACKGROUND Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension. METHODS Involvement of IgG was studied using IgG μ heavy chain-null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell-specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). RESULTS Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow-fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension. CONCLUSIONS Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.

中文翻译：

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补充唾液酸前体 N-乙酰-D-甘露糖胺可打破肥胖和高血压之间的联系。

背景技术与肥胖相关的高血压是一种常见疾病，并且对抗潜在肥胖的尝试常常不成功。我们之前发现，全身缺乏抑制性免疫球蛋白 G (IgG) 受体 FcγRIIB 的小鼠可以免受肥胖引起的高血压。然而，FcγRIIB 如何参与尚不清楚。研究旨在确定 IgG 的改变是否会导致肥胖引起的高血压的发病机制。方法 使用成熟 B 细胞缺陷的 IgG μ 重链缺失小鼠​​并通过 IgG 转移研究 IgG 的参与。在具有整体或内皮细胞特异性受体缺失的小鼠中研究了 FcγRIIB 的参与情况。通过高脂饮食（HFD）诱发肥胖，并通过无线电遥测或尾套测量血压（BP）。通过黑接骨木凝集素印迹法评估小鼠 IgG 上 Fc 聚糖的相对唾液酸化，这会影响 Fc 受体的 IgG 激活。在人主动脉内皮细胞中评估了 IgG 对内皮 NO 合酶的影响。通过质谱法对 3442 名人类参与者的 IgG Fc 聚糖唾液酸化进行了研究，并评估了唾液酸化与血压之间的关系。在给予唾液酸前体 N-乙酰基-D-甘露糖胺 (ManNAc) 的 HFD 喂养小鼠中测定了 IgG 唾液酸化正常化的效果。结果 缺乏 B 细胞的小鼠可以免受肥胖引起的高血压的影响。与对照食物喂养的小鼠的 IgG 相比，HFD 喂养的小鼠的 IgG 唾液酸化程度较低，当转移到缺乏 IgG 的受体时，血压会升高；如果受体缺乏 FcγRIIB，则不会出现高血压反应。神经氨酸酶处理的缺乏 Fc 聚糖末端唾液酸的 IgG 也会升高血压。在培养的内皮细胞中，通过 FcγRIIB，HFD 喂养小鼠的 IgG 和神经氨酸酶处理的 IgG 通过改变内皮 NO 合酶磷酸化来抑制血管内皮生长因子激活内皮 NO 合酶。在人类中，肥胖与较低的 IgG 唾液酸化相关，而收缩压与 IgG 唾液酸化呈负相关。内皮细胞中缺乏 FcγRIIB 的小鼠可以免受肥胖引起的高血压的影响。此外，在 HFD 喂养的小鼠中，ManNAc 使 IgG 唾液酸化正常化并预防肥胖引起的高血压。结论 内皮细胞中的低唾液酸化 IgG 和 FcγRIIB 与肥胖诱发的小鼠高血压密切相关，并且在人类中也获得了支持性证据。针对这些机制的干预措施，例如补充 ManNAc，可能提供打破肥胖和高血压之间联系的新方法。