In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)
Abstract:
Introduction: Lipocalin-2 (Lcn2) is an acute phase protein and a marker of kidney injury. Recently, elevated Lcn2-levels have been reported in heart failure and myocardial infarction. Moreover, stimulation of breast cancer angiogenesis was observed. Thus, we hypothesized that Lcn2 may be a regulator of vascular function and a target for the treatment of ischemic vascular disorders. Methods/Results: In-vitro Lcn2 mediated proliferation of human umbilical vein endothelial cells (HUVEC; rel. proliferation Lcn2 10 nM vs. ctr.: 1.4±0.09, n=3, P 〈 0.001) and human coronary artery endothelial cells (HCAEC; rel. proliferation Lcn2 10 nM vs. ctr.: 1.3±0.07, n=3, P 〈 0.01) as determined by BrdU-incorporation. In the in-vitro matrigel assay stimulation of HUVEC (1.4 fold vs. ctr., n=3, P 〈 0.01) and HCAEC (1.6 fold vs. ctr., n=3, P 〈 0.001) with Lcn2 resulted in a significant induction of capillary like tube formation. All effects were similar to vascular endothelial growth factor (VEGF). Mechanistically these results can be traced back to phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Real-time PCR analyses revealed expression of Lcn2 and its receptor by endothelial cells (EC) as well as a hypoxia-dependent up-regulation (rel. Lcn2 mRNA hypoxia vs. normoxia 1.6±0.2, P 〈 0.05; rel. Lcn2-receptor mRNA hypoxia vs. normoxia 2.6±0.2, P 〈 0.001). In the mouse aortic ring assay Lcn2-treatment resulted in a significant outgrowth of EC similar to VEGF. In the hind limb ischemia (HLI) model Lcn2 -/- mice showed an impressive phenotype. After induction of HLI we detected significantly more tissue defects compared to wild type (WT) mice. The ischemia-related lesions were more severe as determined by necrosis score (necrosis score Lcn2 -/- 1.8±0.2 vs. WT 0.7±0.2, n=5, P 〈 0.01) and amputation rate was significantly higher. In ischemic hind limbs of Lcn2 -/- mice ERK1/2-phosphorylation was almost abrogated which might be an underlying mechanism. Transplantation of WT-bone marrow to irradiated Lcn2 -/- mice didn’t influence the outcome suggesting that observed effects are rather endothelium-dependent than influenced by an inflammatory response. Conclusion: Lcn2 might be a promising therapeutic factor for the treatment of ischemic vascular disorders.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.130.suppl_2.17225
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
1466401-X
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