University of Oulu

Marques, F. Z., Prestes, P. R., Byars, S. G., Ritchie, S. C., Würtz, P., Patel, S. K., Booth, S. A., Rana, I., Minoda, Y., Berzins, S. P., Curl, C. L., Bell, J. R., Wai, B., Srivastava, P. M., Kangas, A. J., Soininen, P., Ruohonen, S., Kähönen, M., Lehtimäki, T., … Charchar, F. J. (2017). Experimental and Human Evidence for Lipocalin‐2 (Neutrophil Gelatinase‐Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and Heart Failure. Journal of the American Heart Association, 6(6).

Experimental and human evidence for lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the development of cardiac hypertrophy and heart failure

Saved in:
Author: Marques, Francine Z.1,2; Prestes, Priscilla R.1; Byars, Sean G.3,4,5;
Organizations: 1School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia, Ballarat, Victoria, Australia
2Heart Failure Research Group, Baker Heart and Diabetes Research Institute, Melbourne, Victoria, Australia
3Centre for Systems Genomics, The University of Melbourne, Victoria, Australia
4School of BioSciences, The University of Melbourne, Victoria, Australia
5Department of Pathology, The University of Melbourne, Victoria, Australia
6Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
7Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
8Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Victoria, Australia
9Department of Physiology, The University of Melbourne, Victoria, Australia
10Department of Cardiology, Austin Health, Heidelberg, Victoria, Australia
11NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
12Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland
13Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland
14Fimlab Laboratories, Department of Clinical Chemistry, Pirkanmaa Hospital District, School of Medicine, University of Tampere, Finland
15National Institute for Health and Welfare, Helsinki, Finland
16Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
17Medical Research Council Integrative Epidemiology Unit, University of Bristol, United Kingdom
18School of Social and Community Medicine, University of Bristol, United Kingdom
19School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
20Department of Cardiovascular Sciences, University of Leicester, United Kingdom
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.7 MB)
Persistent link:
Language: English
Published: John Wiley & Sons, 2017
Publish Date: 2020-04-03


Background: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin‐2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants.

Methods and Results: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2‐knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2‐knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS,LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single‐nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis‐eQTL for LCN2 expression.

Conclusions: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.

see all

Series: Journal of the American Heart Association
ISSN: 2047-9980
ISSN-E: 2047-9980
ISSN-L: 2047-9980
Volume: 6
Issue: 6
Article number: e005971
DOI: 10.1161/JAHA.117.005971
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Copyright information: © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.