Deamidated lipocalin-2 induces endothelial dysfunction and hypertension in dietary obese mice.

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). 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. polyamination facilitates the clearance of lipocalin-2,whereas the accumulation of deamidated lipocalin-2 in arteries causes vascular inflammation,endothelial dysfunction,and hypertension.