TY - JOUR
T1 - Supplementation with the Sialic Acid Precursor N-Acetyl-D-Mannosamine Breaks the Link between Obesity and Hypertension
AU - Peng, Jun
AU - Vongpatanasin, Wanpen
AU - Sacharidou, Anastasia
AU - Kifer, Domagoj
AU - Yuhanna, Ivan S.
AU - Banerjee, Subhashis
AU - Tanigaki, Keiji
AU - Polasek, Ozren
AU - Chu, Haiyan
AU - Sundgren, Nathan C.
AU - Rohatgi, Anand
AU - Chambliss, Ken L.
AU - Lauc, Gordan
AU - Mineo, Chieko
AU - Shaul, Philip W.
N1 - Funding Information:
(G.L.) and the Croatian National Centre of Research Excellence in Personalized Healthcare (grant KK.01.1.1.01.0010) (G.L.). The 10,001 Dalmatians project was supported by the Medical Research Council Human Genetics Unit, the Croatian Ministry of Science, Education and Sports (grant 216-1080315-0302), the European Union framework program 6 EUROSPAN project (contract LSHG-CT-2006-018947), and the Croatian Science Foundation (grant 8875).
Funding Information:
The work was supported by National Institutes of Health grants HL115122 (P.W.S.), DK110127 (C.M.), HL133179 (W.V.), and AG057571 (W.V.), and by the Crystal Charity Ball Center for Pediatric Critical Care Research (P.W.S.), the Hart-well Foundation (P.W.S.), the Pak Center of Mineral Metabolism and Clinical Research (W.V.), and the George M. O’Brien Kidney Research Core Center (National Institutes of Health grant P30-DK079328). Additional support was provided by the European Structural and Investment Funds IRI (grant KK.01.2.1.01.0003)
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/12/10
Y1 - 2019/12/10
N2 - 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.
AB - 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.
KW - N-acetylneuraminic acid
KW - endothelium
KW - hypertension
KW - immunoglobulins
KW - nitric oxide synthase
KW - obesity
KW - receptors, Fc
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U2 - 10.1161/CIRCULATIONAHA.119.043490
DO - 10.1161/CIRCULATIONAHA.119.043490
M3 - Article
C2 - 31597453
AN - SCOPUS:85076329954
SN - 0009-7322
VL - 140
SP - 2005
EP - 2018
JO - Circulation
JF - Circulation
IS - 24
ER -