Deamidated lipocalin-2 induces endothelial dysfunction and hypertension in dietary obese mice.
BACKGROUND
Lipocalin-2 is a proinflammatory adipokine upregulated in obese humans and animals. A pathogenic role of lipocalin-2 in hypertension has been suggested. Mice lacking lipocalin-2 are protected from dietary obesity-induced cardiovascular dysfunctions. Administration of lipocalin-2 causes abnormal vasodilator responses in mice on a high-fat diet (HFD).


RESULTS
Wild-type and lipocalin-2 knockout mice were fed with standard chow or HFD. Immunoassays were performed for evaluating the circulating and tissue contents of lipocalin-2. The relaxation and contraction of arteries were studied using a wire myograph. Blood pressure was monitored with implantable radio telemetry. Dietary obesity promoted the accumulation of lipocalin-2 protein in blood and arteries. Deficiency of this adipokine protected mice from dietary obesity-induced elevation of blood pressure. Mass spectrometry analysis revealed that human and murine lipocalin-2 were modified by polyamination. Polyaminated lipocalin-2 was rapidly cleared from the circulation. Adipose tissue was a major site for lipocalin-2 deamidation. The circulating levels and the arterial accumulation of deamidated lipocalin-2 were significantly enhanced by treatment with linoleic acid (18:2n-6), which bound to lipocalin-2 with high affinity and prevented its interactions with matrix metalloproteinase 9 (MMP9). Combined administration of linoleic acid with lipocalin-2 caused vascular inflammation and endothelial dysfunction and raised the blood pressure of mice receiving standard chow. A human lipocalin-2 mutant with cysteine 87 replaced by alanine (C87A) contained less polyamines and exhibited a reduced capacity to form heterodimeric complexes with MMP9. After treatment, C87A remained in the circulation for a prolonged period of time and evoked endothelial dysfunction in the absence of linoleic acid.


CONCLUSIONS
Polyamination facilitates the clearance of lipocalin-2, whereas the accumulation of deamidated lipocalin-2 in arteries causes vascular inflammation, endothelial dysfunction, and hypertension.
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China.
Erfei
E
Song
Pengcheng
P
Fan
Bosheng
B
Huang
Han-Bing
HB
Deng
Bernard Man Yung
BM
Cheung
Michel
M
Félétou
Jean-Paul
JP
Vilaine
Nicole
N
Villeneuve
Aimin
A
Xu
Paul M
PM
Vanhoutte
Yu
Y
Wang
D000209:Acute-Phase Proteins / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000503:physiopathology; D001794:Blood Pressure; D003641:Deamination; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D019787:Linoleic Acid / Q000008:administration & dosage / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009765:Obesity / Q000150:complications* / Q000503:physiopathology; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014664:Vasodilation
D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C071332:Lcn2 protein, mouse; D019787:Linoleic Acid; D020780:Matrix Metalloproteinase 9
adipokine; endothelial dysfunction; inflammation; lipotoxicity; obesity